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Role of Estrogens in Adipocyte Development and Function
Abstract
Estrogen has historically been viewed as a major regulator of adipose tissue in adult females, but recent work has indicated that estrogen's role in adipose biology may be broader than initially appreciated and has also provided important insights into the mechanism of estrogen effects on adipose tissue. Estrogen has direct effects on adipocytes to inhibit lipogenesis and may also have direct effects on other cellular constituents of adipose tissue, as well as metabolic effects on other target organs that can regulate adipose tissue. Estrogen has central effects on food consumption and energy expenditure that contribute to its overall inhibitory effects on adipose deposition. Estrogen also plays an important role in regulating adipose deposition in males and recently has been shown to be an important factor in the determination of adipocyte number, indicating that it regulates key developmental events in adipogenesis. Although critical questions still remain in our understanding of the overall role of estrogen in adipose tissue, it is clear that estrogen plays a more important role in adipose tissue than originally realized and that it is a major regulator of adipose tissue in both sexes during development and adulthood.
... Notably in those studies, older females with post-operative hepatic steatosis did not respond as well to PERT. This confirms observations from other studies that suggest post-menopausal women have an increased risk of insulin resistance, hyperlipidemia, and visceral fat accumulation which are all risk factors for development of conventional hepatic steatosis due to imbalance of sex hormones metabolism [50][51][52][53]. ...
... Those with benign surgical indications had a lower incidence of de novo NAFLD whereas patients with malignancy had higher incidence. This observation is likely explained by the correlation between decline in BMI and de novo NAFLD suggesting that the pathophysiology is similar to fatty infiltration in malnutrition [50][51][52][53]. Additionally, patients that underwent subtotal stomach preserving PD with Billroth II reconstruction were at increased risk of EPI and de novo NAFLD if they were female or had a BMI greater than 22.5 kg/m 2 [54]. ...
... Additionally, patients that underwent subtotal stomach preserving PD with Billroth II reconstruction were at increased risk of EPI and de novo NAFLD if they were female or had a BMI greater than 22.5 kg/m 2 [54]. Obese patients may be more susceptible to steatosis due to dietary limitation and rapid weight loss from the antrectomy whereas the gender difference may be explained by a majority of these women being post-menopausal so they may not have the protective effect of estrogen on fatty liver disease that has been demonstrated in prior studies [50][51][52][53]. Additionally, atrophy of the pancreas remnant was a significant risk factor for development of steatosis, which improved in a majority of these patients after administration of high dose PERT [47]. ...
Background:
As operative techniques and mortality rates of pancreatectomy have improved, there has been a shift in focus to maintaining and improving the nutritional status of these patients as we continue to learn more about post-operative complications. Although pancreatic endocrine and exocrine insufficiencies are known complications of pancreatectomy, increased longevity of these patients has also led to a higher incidence of de novo fatty liver disease which differs from traditional fatty liver disease given the lack of metabolic syndrome.
Aim:
To identify and summarize patterns and risk factors of post-pancreatectomy de novo fatty liver disease to guide future management.
Methods:
We performed a database search on PubMed selecting papers published between 2001 and 2022 in the English language. PubMed was last accessed 1 June 2022.
Results:
Various factors influence the development of de novo fatty liver including indication for surgery (benign vs malignant), type of pancreatectomy, amount of pancreas remnant, and peri-operative nutritional status. With an incidence rate up to 75%, de novo non-alcoholic fatty liver disease (NAFLD) can develop within 12 mo after pancreatectomy and various risk factors have been established including pancreatic resection line and remnant pancreas volume, peri-operative malnutrition and weight loss, pancreatic exocrine insufficiency (EPI), malignancy as the indication for surgery, and postmenopausal status.
Conclusion:
Since majority of risk factors leads to EPI and malnutrition, peri-operative focus on nutrition and enzymes replacement is key in preventing and treating de novo NAFLD after pancreatectomy.
... Estrogen has been shown to reduce adipogenesis through activation of mTOR signaling, promoting inhibition of PPARg (40,(59)(60)(61)(62) or reduction of autophagy in female VAT (63). Importantly, the pro-lipolytic effect of E2 has been found to be blunted specifically in female SAT (64), via estrogen-mediated increase in anti-lipolytic a2A-adrenergic receptors (59,64). ...
... Estrogen has been shown to reduce adipogenesis through activation of mTOR signaling, promoting inhibition of PPARg (40,(59)(60)(61)(62) or reduction of autophagy in female VAT (63). Importantly, the pro-lipolytic effect of E2 has been found to be blunted specifically in female SAT (64), via estrogen-mediated increase in anti-lipolytic a2A-adrenergic receptors (59,64). Interestingly, this was not observed in VAT (64) which may FIGURE 1 | Effects of estrogen signaling in female and male SAT and VAT. ...
... help to explain why only SAT and not VAT in females is affected by changes in serum levels of estrogen and how estrogen overall has anti-obesity effects but at the same time promotes fat storage subcutaneously (59,64). These effects of estrogen may explain some of the findings in genome-wide association studies with more than 224,000 individuals (65), showing that metabolic changes are likely involved in the sexual dimorphism of obesity and fat distribution, implicating mechanisms via differential control of adipogenesis and insulin resistance between sexes (1,65,66). ...
Sex hormones contribute to differences between males and females in body fat distribution and associated disease risk. Higher concentrations of estrogens are associated with a more gynoid body shape and with more fat storage on hips and thighs rather than in visceral depots. Estrogen-mediated protection against visceral adiposity is shown in post-menopausal women with lower levels of estrogens and the reduction in central body fat observed after treatment with hormone-replacement therapy. Estrogen exerts its physiological effects via the estrogen receptors (ERα, ERβ and GPR30) in target cells, including adipocytes. Studies in mice indicate that estrogen protects against adipose inflammation and fibrosis also before the onset of obesity. The mechanisms involved in estrogen-dependent body fat distribution are incompletely understood, but involve, e.g., increased mTOR signaling and suppression of autophagy and adipogenesis/lipid storage. Estrogen plays a key role in epigenetic regulation of adipogenic genes by interacting with enzymes that remodel DNA methylation and histone tail post-translational modifications. However, more studies are needed to map the differential epigenetic effects of ER in different adipocyte subtypes, including those in subcutaneous and visceral adipose tissues. We here review recent discoveries of ER-mediated transcriptional and epigenetic regulation in adipocytes, which may explain sexual dimorphisms in body fat distribution and obesity-related disease risk.
... Lipedema predominantly affects females and often manifests during time of hormone fluctuations, during puberty, childbirth, or menopause [7,8], indicating that estrogen and estrogen signaling play a role in the pathogenesis of lipedema via direct impacts on adipocytes and immune cells, and/or secondary effects on the brain control centers [9,10]. However, the exact mechanism(s) of action remain unclear [11,12]. ...
... There are three receptors that have distinct presences and functions around the body. Alterations in estrogen activity or the absence of estrogen receptors (ER) results in the accumulation of subcutaneous adipose tissue (SAT), a phenomenon observed in lipedema patients [5,9,13,14]. Szél et al. hypothesized that alteration in ERs is involved in the regulation of appetite and weight gain which might explain why lipedema patients accumulate fat and have difficulty losing it with diet and exercise [10]. ...
... Estrogen exerts its function through the estrogen receptor alpha (ERα) and beta (ERβ). Both ERα and ERβ receptors appear in significantly high concentrations in SAT of premenopausal women, as signaling from estrogens mediates adipose deposition throughout the body [9,16]. However, ERα expression is reduced in the SAT of clinically obese females and postmenopausal women treated with estradiol compared to their normal-weight counterparts [14,17,18]. ...
Lipedema is an underdiagnosed painful adipose tissue disorder that occurs almost exclusively in women, with onset manifesting at puberty or at times of hormonal change. Unlike many fat disorders, diet and exercise have little to no impact on the prevention or progression of this disease. Estrogens control the distribution of body fat and food intake, regulate leptin expression, increase insulin sensitivity, and reduce inflammation through signaling pathways mediated by its receptors, estrogen receptor alpha (ERα) and ERβ. This review will focus on understanding the role of estrogen in the pathogenesis of the disease and envisage potential hormonal therapy for lipedema patients.
... [337][338][339] In the periphery, estrogen can act on ERs to increase insulin sensitivity in adipose tissue, skeletal muscle, and liver. [340][341][342] For example, estrogen can inhibit adipogenesis 341 and reduce the expression of lipoprotein lipase, an important regulator of lipoprotein metabolism. 340 Moreover, an experiment showed that ER agonist therapy increased the expression of GLUT4 and glucose uptake in rat skeletal muscle. ...
... [337][338][339] In the periphery, estrogen can act on ERs to increase insulin sensitivity in adipose tissue, skeletal muscle, and liver. [340][341][342] For example, estrogen can inhibit adipogenesis 341 and reduce the expression of lipoprotein lipase, an important regulator of lipoprotein metabolism. 340 Moreover, an experiment showed that ER agonist therapy increased the expression of GLUT4 and glucose uptake in rat skeletal muscle. ...
s
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
... Beyond lipid metabolism related genes, miR-22 inhibits the estrogen receptor alpha (ERα) expression [59,60], constituting a negative feedback loop because ERα inhibits miR-22 biosynthesis specifically in male mice [61]. ERα signaling is vital for proper adipose tissue function [62,63] and positively regulates adipose tissue browning [64]. Therefore, miR-22 and ERα are important coregulators of beige adipocytes appearance and function and present a sex-specific inter-regulation. ...
... 67,68,79 More specifically, estrogens have been shown to attenuate metabolic dysfunction and NAFLD due to their effects on hepatic lipogenic and inflammatory signaling and energy balance (eg, regulation of food intake, energy expenditure, direct effects on the physiology of energy metabolism-regulating organs such as liver, muscle, adipose tissue and pancreas). [80][81][82][83][84][85][86][87][88] At the initiation of the experiment, the mice were randomly divided into the following groups: Chow Diet, HF DMSO (10% v/v), and HF IOI-214 (1 mg/kg) in 10% DMSO. The mice were then placed on either a chow diet consisting of 10% fat, 20% protein, 70% carbohydrate [(#D12450B, Research Diets Inc., New Brunswick, NJ, USA), or a HF diet consisting of 60% fat, 20% protein, 20% carbohydrate [(#D12492, Research Diets Inc., New Brunswick, NJ, USA)]. ...
Purpose
Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic (dysfunction) associated fatty liver disease (MAFLD), is the most common chronic liver disease in the United States. Presently, there is an intense and ongoing effort to identify and develop novel therapeutics for this disease. In this study, we explored the anti-inflammatory activity of a new compound, termed IOI-214, and its therapeutic potential to ameliorate NAFLD/MAFLD in male C57BL/6J mice fed a high fat (HF) diet.
Methods
Murine macrophages and hepatocytes in culture were treated with lipopolysaccharide (LPS) ± IOI-214 or DMSO (vehicle), and RT-qPCR analyses of inflammatory cytokine gene expression were used to assess IOI-214’s anti-inflammatory properties in vitro. Male C57BL/6J mice were also placed on a HF diet and treated once daily with IOI-214 or DMSO for 16 weeks. Tissues were collected and analyzed to determine the effects of IOI-214 on HF diet-induced NAFL D/MAFLD. Measurements such as weight, blood glucose, serum cholesterol, liver/serum triglyceride, insulin, and glucose tolerance tests, ELISAs, metabolomics, Western blots, histology, gut microbiome, and serum LPS binding protein analyses were conducted.
Results
IOI-214 inhibited LPS-induced inflammation in macrophages and hepatocytes in culture and abrogated HF diet-induced mesenteric fat accumulation, hepatic inflammation and steatosis/hepatocellular ballooning, as well as fasting hyperglycemia without affecting insulin resistance or fasting insulin, cholesterol or TG levels despite overall obesity in vivo in male C57BL/6J mice. IOI-214 also decreased systemic inflammation in vivo and improved gut microbiota dysbiosis and leaky gut.
Conclusion
Combined, these data indicate that IOI-214 works at multiple levels in parallel to inhibit the inflammation that drives HF diet-induced NAFLD/MAFLD, suggesting that it may have therapeutic potential for NAFLD/MAFLD.
... It was previously demonstrated by Nomelí P. Núñez's group that female mice are less likely to become obese than male mice [34]. When the ovary was removed from female mice via ovariectomy, they became obese, and the obesity was reversed through the administration of external estrogen [35,36]. Therefore, female obese models are more challenging to establish due to the protective role of estrogen in female animals. ...
Obesity is one of the main risk factors for cardiovascular diseases, type II diabetes, hypertension, and certain cancers. Obesity in women at the reproductive stage adversely affects contraception, fertility, maternal well-being, and the health of their offspring. Being a major protein component in chylomicrons and high-density lipoproteins, apolipoprotein A-IV (apoA-IV) is involved in lipid metabolism, food intake, glucose homeostasis, prevention against atherosclerosis, and platelet aggregation. The goal of the present study is to determine the impact of apoA-IV deficiency on metabolic functions in 129X1/SvJ female mouse strain. After chronic high-fat diet feeding, apoA-IV−/− mice gained more weight with a higher fat percentage than wild-type (WT) mice, as determined by measuring their body composition. Increased adiposity and adipose cell size were also observed with a microscope, particularly in periovarian fat pads. Based on plasma lipid and adipokine assays, we found that obesity in apoA-IV−/− mice was not associated with hyperlipidemia but with higher leptin levels. Compared to WT mice, apoA-IV deficiency displayed glucose intolerance and elevated insulin levels, according to the data of the glucose tolerance test, and increased HOMA-IR values at fasting, suggesting possible insulin resistance. Lastly, we found obesity in apoA-IV−/− mice resulting from reduced energy expenditure but not food intake. Together, we established a novel and excellent female mouse model for future mechanistic study of obesity and its associated comorbidities.
... Adipose tissue metabolism is modulated by hormones, including sex hormones [19]. The effect of endocrine-disrupting chemicals is widespread and may affect lipogenesis, lipolysis, and adipogenesis [20]. A recent cohort study reported a statistically significant inverse association between PFAS concentrations and resting metabolic rate, which may contribute to increased weight gain or interference with weight loss [12]. ...
Introduction
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are potentially obesogenic for children. We undertook a systematic review to synthesize this literature and explore sources of heterogeneity in previously published epidemiological studies.
Methods
Studies that collected individual-level PFAS and anthropometric data from children up to 12 years of age were identified by searching six databases. We excluded studies that only evaluated obesity measures at the time of birth. A full-text review and quality assessment of the studies was performed using the Office of Health Assessment and Translation (OHAT) criteria. Forest plots were created to summarize measures of association and assess heterogeneity across studies by chemical type and exposure timing. Funnel plots were used to assess small-study effects.
Results
We identified 24 studies, of which 19 used a cohort design. There were 13 studies included in the meta-analysis examining various chemicals and outcomes. Overall prenatal exposures to four different types of PFAS were not statistically associated with changes in body mass index (BMI) or waist circumference. In contrast, for three chemicals, postnatal exposures were inversely related to changes in BMI (i.e., per log10 increase in PFOS: BMI z-score of −0.16 (95% CI: −0.22, −0.10)). There was no substantial heterogeneity in the reported measures of association within prenatal and postnatal subgroups. We observed modest small-study effects, but correction for these effects using the Trim and Fill method did not change our summary estimate(s).
Conclusion
Our review found no evidence of a positive association between prenatal PFAS exposure and pediatric obesity, whereas an inverse association was found for postnatal exposure. These findings should be interpreted cautiously due to the small number of studies. Future research that can inform on the effects of exposure mixtures, the timing of the exposure, outcome measures, and the shape of the exposure-response curve is needed.
... One possible explanation was that multiple biological mechanisms may underlie the associations we observed between body fat distribution and sustained BP elevation. Estrogen can directly or through its receptor activation in adipocytes and adipose tissue to promote adipose tissue deposition, while androgen can affect the number of adipocytes and adipose tissue distribution (Cooke and Naaz 2004;Palmer and Clegg 2015). On the other hand, one study indicated that girls had higher adrenal androgen concentrations and greater adiposity than boys throughout childhood, which accounted for the differences in insulin sensitivity (Ayyavoo et al. 2014). ...
Background
To investigate the associations between body fat distribution and high blood pressure (HBP) in children and adolescents with different nutritional status.
Methods
Data of the present analysis came from a cross-sectional survey of 1423 children and adolescents (50.2% boys) aged 7–17 years conducted in Beijing, China. Pearson partial correlation coefficients between DXA (dual-energy X-ray absorptiometry)-derived fat indicators and anthropometric measures. Logistic regression was conducted to relate the risk of HBP and quartiles of fat indicators of various body fat distributions. Trend analysis was performed to explore the dose-response relationship between HBP risk and regional fat distribution.
Results
Among all participants, boys generally have a higher prevalence of HBP (18.0% to 46.9%) than girls (17.3% to 35.1%) do in both non-overweight and overweight groups. In non-overweight, HBP was significantly associated with body fat distribution for every interquartile increase in girls. Specifically, we found that the ratio of T/L (trunk fat mass/leg fat mass) and A/G (android fat mass/gynoid fat mass) were significant predictors of HBP in overweight boys, with ORs of 8.24 (95%CI 3.00, 22.61) and 2.78 (95%CI 1.27, 6.09), respectively.
Conclusions
Higher quartiles of body fat distribution were positively associated with HBP risk in non-overweight girls, whereas for boys, T/L and A/G fat mass could be more associated with HBP risk.
... At the core of this process is lipoprotein lipase (LPL), an enzyme that catalyses the rate-limiting step in the hydrolysis of circulating lipoproteins. Studies investigating the role of oestrogens in regulating adipose LPL synthesis have been mixed, with some studies supporting findings that oestrogens decrease LPL function, while others suggest that oestrogens do not alter LPL activity [114,115]. For instance, a study in females found that LPL production decreases in gonadal adipose tissue when treated with oestrogens [116,117]. ...
Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue ‘health’. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues.
This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part I)’.
... Estrogen treatment not only affects the skeleton in male mice, but also several other tissues. E2 treatment is known to decrease thymus weight 44 and fat mass in males 45 . Interestingly, the responses to pharmacological E2 treatment were similar in these non-skeletal tissues, as well as in liver, between S122A and WT males. ...
Estrogen receptor alpha (ERα) signaling has beneficial skeletal effects in males. ERα signaling also affects other tissues, and to find bone-specific treatments, more knowledge regarding tissue-specific ERα signaling is needed. ERα is subjected to posttranslational modifications, including phosphorylation, which can influence ERα function in a tissue-specific manner. To determine the importance of phosphorylation site S122 (corresponding to human ERα site S118) for the skeleton and other tissues, male mice with a S122A mutation were used. Total areal bone mineral density was similar between gonadal intact S122A and WT littermates followed up to 12 months of age, and weights of estrogen-responsive organs normalized for body weight were unchanged between S122A and WT males at both 3 and 12 months of age. Interestingly, 12-month-old S122A males had decreased body weight compared to WT. To investigate if site S122 affects the estrogen response in bone and other tissues, 12-week-old S122A and WT males were orchidectomized (orx) and treated with estradiol (E2) or placebo pellets for four weeks. E2 increased cortical thickness in tibia in both orx WT (+ 60%, p < 0.001) and S122A (+ 45%, p < 0.001) males. However, the E2 effect on cortical thickness was significantly decreased in orx S122A compared to WT mice (− 24%, p < 0.05). In contrast, E2 affected trabecular bone and organ weights similarly in orx S122A and WT males. Thus, ERα phosphorylation site S122 is required for a normal E2 response specifically in cortical bone in male mice, a finding that may have implications for development of future treatments against male osteoporosis.
... Adipocytes have previously been shown to express ERs and respond to circulating estrogen levels 28,29 . However, variation of adipocyte numbers in endothelial mutants (see adipocyte phenotypes of Esr1 iΔEC , Gper1 iΔEC and Cpt1a iΔEC mice) prompted us to investigate the expression of lipolytic enzymes in these mutants. ...
The mammalian skeletal system shows sex differences in structure, functions, aging and disease incidences. The role of blood vessels in physiological, regenerative and pathological bone functions indicates the requisite to understanding their sex specificity. In this study, we found that estrogen regulates blood vessel physiology during pregnancy and menopause through estrogen receptor alpha (ERα) and G-protein-coupled estrogen receptor-1 (GPER1) but not ERβ-dependent signaling in mice. Estrogen regulates the lipid use of bone endothelial cells (BECs) and promotes lipolysis of adipocytes and fatty acid (FA) uptake from the microenvironment. Low estrogen conditions skew endothelial FA metabolism to accumulate lipid peroxides (LPOs), leading to vascular aging. High ferrous ion levels in female BECs intensify LPO accumulation and accelerate the aging process. Notably, inhibiting LPO generation using liproxstatin-1 in aged mice significantly improved bone heath. Thus, our findings demonstrate the effects of estrogen on BECs and suggest that LPO targeting could be an efficient strategy to manage blood and bone health in females.
... 2,3 Low bone mass, sarcopenia and obesity have common pathogenetic factors, such as chronic low-grade inflammation, inadequate nutrition, endocrine disorders, low level of physical activity, and neuromuscular disregulation. 1 Estrogens have a protective role for muscle and bone, and estrogens depletion after menopause may explain the natural increase in adipogenesis, weight gain, and accelerated loss of muscle and bone mass. 4 Adipose tissue, and particularly visceral fat, generates many adipokines, such as leptin, whose receptors are expressed by osteoblasts and myocytes, that could maintain a low-grade inflammatory milieu, contributing to worsening of several clinical conditions, including obesity, osteoporosis and sarcopenia. 5,6,7 For years, it has been hypothesized that obesity exerted protection against bone loss after menopause, 8 but recently Nielson et al. ...
... ADSCs are considered a promising method for the treatment of intrinsic sphincter deficiency due to urethral sphincter weakness and subsequent sphincter reconstruction [302,303]. 17β-E2 has been shown to regulate the multidifferentiation ability of stem cells in bone, muscle, cartilage, and adipose tissue [304][305][306]. Based on this information, Feng's group developed a poly(l-lactide)/poly(e-caprolactone) electrospun nanoscaffold to combine ADSCs and E2 [307]. ...
Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation.
Graphical Abstract
... Human adipose tissue contains both membrane and nuclear estrogen receptors [76]. They can impact metabolic health by inhibiting adipocyte lipogenesis and modulation of energy expenditure and food consumption via actions on the brain [77]. Estrogens promote preadipocyte proliferation and regulate adipocyte number [78,79], presumably mediated by insulin growth factor (IGF) 1 receptor (IGF1-R) and PPARγ [78]. ...
... Human adipose tissue contains both membrane and nuclear estrogen receptors [76]. They can impact metabolic health by inhibiting adipocyte lipogenesis and modulation of energy expenditure and food consumption via actions on the brain [77]. Estrogens promote preadipocyte proliferation and regulate adipocyte number [78,79], presumably mediated by insulin growth factor (IGF) 1 receptor (IGF1-R) and PPARγ [78]. ...
https://www.sciencedirect.com/science/article/pii/S0006295222002386
... Sex steroids also appear to impact adipogenic potential; however, this appears to be less straightforward. Studies have shown that estrogen can inhibit and promote adipogenesis in vitro (132,232,233). These differences in adipogenic action in response to estrogen may reflect estradiol concentrations, timing, type of APC tested (subcutaneous vs. visceral APC), or cell line (3T3-L1). ...
Obesity and its’ associated metabolic diseases such as type 2 diabetes and cardiometabolic disorders are significant health problems confronting many countries. A major driver for developing obesity and metabolic dysfunction is the uncontrolled expansion of white adipose tissue (WAT). Specifically, the pathophysiological expansion of visceral WAT is often associated with metabolic dysfunction due to changes in adipokine secretion profiles, reduced vascularization, increased fibrosis, and enrichment of pro-inflammatory immune cells. A critical determinate of body fat distribution and WAT health is the sex steroid estrogen. The bioavailability of estrogen appears to favor metabolically healthy subcutaneous fat over visceral fat growth while protecting against changes in metabolic dysfunction. Our review will focus on the role of estrogen on body fat partitioning, WAT homeostasis, adipogenesis, adipocyte progenitor cell (APC) function, and thermogenesis to control WAT health and systemic metabolism.
... Oestradiol is the critical hormone that brings about epiphyseal closure thereby causing early advancement of BA in girls in puberty [27]. Girls have a greater percentage of body fat than boys [28]. Serum levels of leptin rise throughout puberty to reach higher levels in females than males, whereas, levels of the antilipolytic adipocytokine adiponectin remains stable in females but falls in males in response to androgen leading to advanced bone age in girls as compared to boys [29]. ...
Introduction:
Bone age (BA) is a quantitative determination of skeletal maturation. The role of puberty in variations in BA is poorly understood as hypothalamic-pituitary-gonadal (HPG) axis maturation and skeletal maturation are regulated in parallel but independently by multiple different factors. In countries like India where there is rapid nutrition transition and increase in prevalence of obesity, their impact on height and BA is not well understood.
Objectives:
To study if in 2-17 year old healthy children, the difference between chronological age (CA), height age (HA) and BA is less than 1 year on either side of the chronological age and to assess relationship of BA with height, weight and BMI with special reference to gender and puberty.
Methods:
This cross-sectional study included 804 preschool/school-going Indian children. Anthropometric measurements and pubertal assessments were performed using standard protocols and were converted to age and sex standardized z-scores using Indian references while BA was estimated by Tanner-Whitehouse (TW3) method. p<0.05 was considered statistically significant.
Results:
The mean age and gender standardized z-scores for height, weight, body mass index (BMI) and BA were -0.3 ± 0.7, -0.7 ± 0.8, -0.1 ± 1.0, and -0.2 ± 0.9 respectively. HA was more delayed in girls while BA was more delayed in boys. The mean BA z-score increased with increasing BMI. After the onset of puberty, there was higher increment in BA in girls and HA in boys (p<0.05).
Conclusions:
HA, BA and CA were tightly correlated in healthy Indian children with a significant role of nutritional status and puberty in causing variation in the same.
... Human adipose tissue contains both membrane and nuclear estrogen receptors [76]. They can impact metabolic health by inhibiting adipocyte lipogenesis and modulation of energy expenditure and food consumption via actions on the brain [77]. Estrogens promote preadipocyte proliferation and regulate adipocyte number [78,79], presumably mediated by insulin growth factor (IGF) 1 receptor (IGF1-R) and PPARγ [78]. ...
Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.
... Estrogen replacement therapy may reduce this weight gain [169]. Estrogens act on adipocytes to inhibit lipogenesis and help modulate energy expenditure and food consumption [170]. Studies have described a role for estrogens in promoting preadipocyte proliferation and regulating adipocyte number in various depots [171,172], presumably mediated by IGF-1R and PPARγ [171]. ...
Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the “obesogen hypothesis” (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
... Premenopausal females accumulate adipose tissue in the gluteal region and subcutaneous tissue, whereas males tend to deposit fat in the abdomen (27,28). Mutations in the PPARG gene could inhibit the differentiation of adipocytes, and lead to lipoatrophy. ...
Purpose
Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disease. Patients typically present with loss of adipose tissue and metabolic complications. Here, we reported a Chinese FPLD3 patient with a novel PPARG gene mutation.
Methods
A 16-year-old female patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequencing was performed by using the extracted DNA. Moreover, we identified FPLD3 patients from previous studies, and according to the protein region affected by the gene mutation. We divided the patients into the DNA-binding domain (DBD) group or the ligand-binding domain (LBD) group, and compared the clinical features between the two groups.
Results
We identified a novel gene mutation affecting the LBD of PPARγ c.929T > C (p.F310S). This mutation leads to the substitution of a phenylalanine by a serine. In our case, subcutaneous fat was significantly diminished in her face, hips and limbs. The patient was also presented with insulin resistance, diabetes mellitus, hypertriglyceridemia, fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy. After literature review, a total of 58 FPLD3 patients were identified and we found no difference in clinical features between the DBD group and LBD group (all P > 0.05).
Conclusions
A Chinese FPLD3 patient with a novel PPARG gene mutation is described. Our case emphasized the importance of physical examination and genetic testing in young patients with severe metabolic syndromes.
... Thus, treatment effects of the SERM Las on thymus is dependent on functional mERα signaling. E2 treatment suppresses fat development and results in decreased fat content in both humans and rodent models (Gambacciani et al. 1997, Cooke & Naaz 2004, Stubbins et al. 2012, and the SERMs Las and Bza have been shown to have estrogen agonistic effects on adipose tissue leading to a decrease in body fat (Ke et al. 1998. However, in this study, we only saw a significant reduction in total body fat percentage in control mice after E2 treatment. ...
Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To determine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza) or estradiol (E2), and various tissues were evaluated.
Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on uterus was predominantly mERα-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were absent in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in the skeleton are mERα-dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrating mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating an ability of these treatments to affect fat tissue in the absence of functional mERα signaling.
In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manner. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.
... Obesity is defined as the excessive accumulation of WAT. The role of sex hormones in obesity and disease has been recognized for decades (Seidell et al. 1990, Marin & Arver 1998, Jones et al. 2000, Cooke & Naaz 2004. Sex hormones influence many aspects that can lead to obesity including food intake, energy expenditure, and the expansion of WAT (Ramirez 1980, Wurtman & Baum 1980, Dubuc 1985, Heine et al. 2000, Musatov et al. 2007, Krause et al. 2021. ...
Sex hormones play a pivotal role in physiology and disease. Estrogen, the female sex hormone, has been long implicated in having protective roles against obesity. However, the direct impact of estrogens in white adipose tissue (WAT) function and growth are not understood. Here, we show that deletion of estrogen receptor alpha (ERα) from adipocytes using Adiponectin-cre does not affect adipose mass in male or female mice under normal or high-fat diet (HFD) conditions. However, loss of ERα in adipocyte precursor cells (APs) via PdgfRα-cre leads to exacerbated obesity upon HFD feeding in both male and female mice, with subcutaneous adipose (SWAT)-specific expansion in male mice. Further characterization of these mice revealed infertility and increased plasma levels of sex hormones, including estradiol in female mice and androgens in male mice. These findings compromise the study of estrogen signaling within the adipocyte lineage using the PdgfRα-cre strain. However, AP transplant studies demonstrate that the increased AP hyperplasia in male SWAT upon PdgfRα-cre-mediated ablation of ERα is not driven by AP-intrinsic mechanisms, but are rather mediated by off-target effects. These data highlight the inherent difficulties in studying models that disrupt the intricate balance of sex hormones. Thus, better approaches are needed to study the cellular and molecular mechanisms of sex hormones in obesity and disease.
... OVX eliminates ovarian estrogens and raises FSH due to the loss of negative feedback from E 2 . OVX is associated with increased body weight and abdominal adiposity when compared with animals that undergo sham surgery (23)(24)(25). Although increased body weight and abdominal adiposity is caused by a combination of increased energy intake and/or decreased energy expenditure, the regulation of energy intake by E 2 appears to differ in mice and rats, such that OVX increased energy intake in rats but not mice. ...
Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause—known as the menopause transition (or perimenopause)—changes in hormones and body composition increase a woman’s overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life‐span are adequately represented.
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... Pre-clinical studies utilising ovariectomised murine models also support a causative relationship between reduced estrogen production, increased VAT mass and the development of NASH (42,(66)(67)(68) . Whilst an in-depth discussion of the role of estrogen within WAT is beyond the scope of this review (see other relevant reviews (42,69,70) ), it is thought that the increased expression of estrogen receptor alpha (ERα) in the gluteal femoral SAT of premenopausal women promotes lipoprotein lipase activity and accumulation of TAG in adipocytes within this depot (71) . Thus, it is likely that differences in WAT function (partly driven by differences in sex hormone concentrations and the expression of functional target receptors) ...
p>In recent years, a wealth of factors are associated with increased risk of developing non-alcoholic fatty liver disease (NAFLD) and NAFLD is now thought to increase the risk of multiple extra-hepatic diseases. The aim of this review is firstly to focus on the role of ageing and sex as key, poorly understood risk factors in the development and progression of NAFLD. Secondly, we aim to discuss the roles of white adipose tissue (WAT) and intestinal dysfunction, as producers of extra-hepatic factors known to further contribute to the pathogenesis of NAFLD. Finally, we aim to summarise the role of NAFLD as a multi-system disease affecting other organ systems beyond the liver. Both increased age and male sex increase the risk of NAFLD and this may be partly driven by alterations in the distribution and function of WAT. Similarly, changes in gut microbiota (GM) composition and intestinal function with ageing and chronic overnutrition are likely to contribute to the development of NAFLD both directly (i.e. by affecting hepatic function) and indirectly via exacerbating WAT dysfunction. Consequently, the presence of NAFLD significantly increases the risk of various extra-hepatic diseases including cardiovascular disease, type 2 diabetes mellitus, chronic kidney disease and certain extra-hepatic cancers. Thus changes in WAT and intestinal function with ageing and chronic overnutrition contribute to the development of NAFLD - a multi-system disease that subsequently contributes to the development of other chronic cardiometabolic diseases.</p
... This main effect resulted in OVX rats being the most obese in the study; the brief period of increased food intake is likely due to the fact that ovarian hormones have direct effects on adipose tissues and indirect effect on regulation of feed intake and energy expenditure via hypothalamus. (42,43) Similar results were also found in other animal studies (44,45) and corresponding human studies in which postmenopausal women increased their food intake and weight a few years after the onset of menopause, (46) alterations in metabolism that likely can be attributed to hormonal changes. ...
Obesity is considered to impair long‐term health by disturbing multiple physiological functions. However, it remains controversial issue, as to whether obesity has beneficial or detrimental effects on bone health in post‐menopausal women. The aims of this study were to investigate the relationships between obesity and bone mineral density (BMD) under conditions of ovarian hormone deficiency in an animal model and to evaluate the potential health benefits of Greenshell™ mussel (GSM) on bone health. A total of 144 adult female Sprague–Dawley rats were fed from age 12 weeks on one of four diets (normal (ND); ND + GSM; high fat/high sugar (HF/HS); HF/HS + GSM; N = 36 per diet). At age 20 weeks, following a DXA scan, 12 of the rats on each diet underwent ovariectomy (OVX) and the remaining rats were left intact. 12 of the intact rats in each diet group were culled at age 26 weeks (Short‐term cohort). The remaining rats were culled at age 48 weeks (Long‐term cohort). Rats were DXA scanned prior to cull then various fat pads were dissected. The results revealed that HF/HS rats and OVX rats dramatically increased body weight and fat deposition in correlation with leptin. In the long term cohort, vertebral spine BMD rapidly declined after OVX. At termination, the OVX rats had decreased plasma bone turnover markers of CIX‐1 and TRAP when compared to sham rats. Significantly higher BMD was found in OVX rats fed HF/HS diet when compared to ND but this difference was not recapitulated in intact rats. BMD of right femur was significantly increased 5–10% by GSM in the short term cohort. The data demonstrated that obesity can be beneficial by increasing BMD in OVX rats, and this may extrapolate to post‐menopausal women as adipocyte‐produced estrogen may slightly compensate for the reduction in ovarian hormones. Finally, the data showed that GSM may be beneficial to bone health by increasing BMD accrual. This article is protected by copyright. All rights reserved.
... For example, many EDCs affect the regulation of sex hormones, the hypothalamic-pituitary-thyroid (HPT) axis, or other endocrine pathways [6,10]. Changes in androgen and estrogen levels (sex hormones) influence lipid accumulation and can cause obesity [11,12]. For example, estrogens control subcutaneous fat accumulation [13] and xenoestrogens, such as hexachlorocyclohexanes, are linked to the development of metabolic abnormalities in obese women [14]. ...
Perchlorate is a water-soluble contaminant found throughout the United States and many other countries. Perchlorate competitively inhibits iodide uptake at the sodium/iodide symporter, reducing thyroid hormone synthesis, which can lead to hypothyroidism and metabolic syndromes. Chronic perchlorate exposure induces hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) in developing threespine stickleback ( Gasterosteus aculeatus ). We hypothesized that perchlorate would also induce zebrafish ( Danio rerio ) to develop phenotypes consistent with NAFLD and to accumulate lipids throughout the body. We exposed zebrafish embryos to four concentrations of perchlorate treated water (10μg/L, 10mg/L, 30mg/L, and 100mg/L) and a control (0mg/L) over the course of 133 days. Adult zebrafish were euthanized, sectioned, H&E and Oil Red-O stained, and analyzed for liver morphology and whole body lipid accumulation. In a representative section of the liver, we counted the number of lipid droplets and measured the area of each droplet and the total lipid area. For whole body analysis, we calculated the ratio of lipid area to body area within a section. We found that zebrafish exposed to perchlorate did not differ in any measured liver variables or whole body lipid area when compared to controls. In comparison to stickleback, we see a trend that control stickleback accumulate more lipids in their liver than do control zebrafish. Differences between the species indicate that obesogenic effects due to perchlorate exposure are not uniform across fish species, and likely are mediated by evolutionary differences related to geographic location. For example, high latitude fishes such as stickleback evolved to deposit lipid stores for over-winter survival, which may lead to more pronounced obesogenic effects than seen in tropical fish such as zebrafish.
... Estrogens have multifunctional roles that in uence growth, differentiation, and metabolism of several tissue types [54][55][56][57] . Estrogens also exert regulatory functions via estrogen receptors ER-α and ER-β, which exist on multiple types of cells, including MSCs 58-61 . ...
Purpose: We retrospectively analysed a cohort of patients treated at our Centre with bone marrow concentrated (BMC) injection for aneurysmal bone cyst (ABC) of the spine, in order to propose this treatment as a valid alternative for the management of ABCs.
Methods: Fourteen patients (6 male, 8 female) were treated between June 2014 to December 2019 with BMC injection for ABC of the spine. The mean age was 17.85 years. The mean follow up was 37.4 months (range 12- 60 months). The dimension of the cyst and the degree of ossification were measured by Computed Tomography (CT) scans before the treatment and during follow-up visits.
Results: Six patients received a single dose of BMC, five patients received two doses and in three patients three doses of BMC were administered. The mean ossification of the cyst (expressed in Hounsfield units) increased statistically from 43.48±2.36 HU to 161.71±23.48 HU during follow-up time and the ossification was associated to an improvement of the clinical outcomes. The mean ossification over time was significantly higher in patients treated with a single injection compared to patients treated with multiple injections. No significant difference in ossification was found between cervical and non-cervical localization of the cyst. Moreover, the initial size of the cyst was not statistically associated with the degree of ossification during follow-up
Conclusions: Results of this paper reinforce our previous evidence on the use of BMC as a valid alternative for spinal ABC management when SAE treatment is contraindicated or ineffective.
... Estrogen may support subcutaneous deposition of adi-pose, thus leading to increased subcutaneous fat and total body fat in women as compared to men [36]. Before menopause, the accumulation of visceral fat among women appears to be inhibited. ...
Background: Non-alcoholic fatty liver disease (NAFLD) has long been considered to be most prevalent chronic hepatic disease. However, the overall prevalence of NAFLD in postmenopausal women was largely unknown. Objectives: In the current study, we aimed to investigate the overall prevalence of NAFLD in postmenopausal women in order to provide more information for clinical work. Methods: A systematic search was conducted in Medline, Embase, web of science and Cochrane for articles in the English language from inception until May 2020. Wilson score method was used to calculate the 95% confidence interval (95% CI) and DerSimonian-Laird random-effects model with Freeman-Tukey double arcsine transformation was used for estimating pooled overall prevalence. Results: Our search returned 4465 records. After removed duplicates and screened titles, abstract and full content of articles, 25 studies were retrieved. Overall, the NAFLD prevalence was 30.81% (95% CI 24.75-37.22). The prevalence of NAFLD in postmenopausal women was 31.64% (95% CI 25.82-37.77) in Asia countries compared to 27.99% (95% CI 11.21- 48.72) in Non-Asia countries. Ultrasound was the most commonly used diagnostic technique in diagnosing NAFLD in postmenopausal women, lead a higher prevalence of NAFLD (32.77%, 95% CI 27.43- 38.35) than computed tomography (CT, 5.64%, 95% CI 4.82-6.52) or fatty live index (FLI, 17.33%, 95% CI 11.72-23.78, P<0.01). Conclusion: Approximately one third of postmenopausal women presented with NAFLD indicated a rather high prevalence which call for the attention of primary care physicians, specialists, and health policy makers.
Hormonal contraceptives are widely prescribed due to their effectiveness and convenience and have become an integral part of family planning strategies worldwide. In the United States, approximately 65% of reproductive-aged women are estimated to be using contraceptive options, with approximately 33% using one or a combination of hormonal contraceptives. While these methods have undeniably contributed to improved reproductive health, recent studies have raised concerns regarding their potential effect on metabolic health. Despite widespread anecdotal reports, epidemiological research has been mixed as to whether hormonal contraceptives contribute to metabolic health effects. As such, the goals of this study were to assess the adipogenic activity of common hormonal contraceptive chemicals and their mixtures. Five different models of adipogenesis were used to provide a rigorous assessment of metabolism-disrupting effects. Interestingly, every individual contraceptive (both estrogens and progestins) and each mixture promoted significant adipogenesis (eg, triglyceride accumulation and/or preadipocyte proliferation). These effects appeared to be mediated in part through estrogen receptor signaling, particularly for the contraceptive mixtures, as cotreatment with fulvestrant acted to inhibit contraceptive-mediated proadipogenic effects on triglyceride accumulation. In conclusion, this research provides valuable insights into the complex interactions between hormonal contraceptives and adipocyte development. The results suggest that both progestins and estrogens within these contraceptives can influence adipogenesis, and the specific effects may vary based on the receptor disruption profiles. Further research is warranted to establish translation of these findings to in vivo models and to further assess causal mechanisms underlying these effects.
By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)‐induced osteoporosis. Results confirm OVX‐induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole‐body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor‐BB and leukemia inhibitory factor, with downregulation of interleukin‐1 R6, and receptor activator of nuclear factor kappa‐B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor‐beta/SMAD, and Wingless‐related integration site/be‐catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo‐osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX‐induced bone loss.
Adipocytes are derived from pluripotent mesenchymal stem cells and can develop into several cell types including adipocytes, myocytes, chondrocytes, and osteocytes. Adipocyte differentiation is regulated by a variety of transcription factors and signaling pathways. Various epigenetic factors, particularly histone modifications, play key roles in adipocyte differentiation and have indispensable functions in altering chromatin conformation. Histone acetylases and deacetylases participate in the regulation of protein acetylation, mediate transcriptional and post-translational modifications, and directly acetylate or deacetylate various transcription factors and regulatory proteins. The adipocyte differentiation of stem cells plays a key role in various metabolic diseases. Cancer stem cells(CSCs) play an important function in cancer metastasis, recurrence, and drug resistance, and have the characteristics of stem cells. They are expressed in various cell lineages, including adipocytes. Recent studies have shown that cancer stem cells that undergo epithelial-mesenchymal transformation can undergo adipocytic differentiation, thereby reducing the degree of malignancy. This opens up new possibilities for cancer treatment. This review summarizes the regulation of acetylation during adipocyte differentiation, involving the functions of histone acetylating and deacetylating enzymes as well as non-histone acetylation modifications. Mechanistic studies on adipogenesis and acetylation during the differentiation of cancer cells into a benign cell phenotype may help identify new targets for cancer treatment.
Dyslipidemia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The interaction between post-transplant hyperlipidemia and acute graft-versus-host disease (aGVHD) is uncertain. In this study, we performed a retrospective study to explore the relationship between dyslipidemia and aGVHD and the potential mechanism of aGVHD on dyslipidemia in 147 recipients who underwent allo-HSCT. The lipid profiles, transplantation details, and other laboratory data of the subjects were collected in the first 100 days post-transplantation. Our results indicated 63 patients with new-onset hypertriglyceridemia and 39 patients with new-onset hypercholesterolemia. A total of 57 (38.8%) patients developed aGVHD after transplantation. In a multifactorial analysis, aGVHD was an independent factor in the development of dyslipidemia in recipients (P < 0.05). After transplantation, the median LDL-C level of patients with aGVHD was 3.04 mmol/L (standard deviation value (SD): 1.36 mmol/L, 95% confidence interval (CI): 2.62, 3.45 mmol/L), and the LDL-C level in patients without aGVHD was 2.51 mmol/L (SD: 1.38 mmol/L, CI: 2.67, 3.40 mmol/L) (P < 0.05). Female recipients had higher lipid levels than males (P < 0.05). LDL levels (≥ 3.4 mmol/L) post-transplant were an independent risk factor for the development of aGVHD (OR = 0.311, P < 0.05). In conclusion, larger sample studies are anticipated to confirm our preliminary result, and an accurate mechanism between lipid metabolism and aGVHD needs to be determined in the future.
Endometriosis is an estrogen-dependent gynecological disease with chronic pelvic inflammation. In order to study the pathophysiology of endometriosis and examine the therapeutic effects of new pharmaceuticals for endometriosis treatment, different animal models had been developed in the last two decades, especially mouse models. However, no study evaluated the effects of various modeling approaches on pathology and immunology in endometriosis. This study aimed to compare endometriotic lesion development and immune profiles under different methods of establishing endometriosis models in mice, including estrus synchronization (ovariectomy with estrogen supplement versus male urine-soaked transfer bedding), endometrium preparations (whole uterus including endometrium and myometrium fragments versus solely endometrium fragments), and surgical transplantation (subcutaneous transplantation versus intraperitoneal injection). Our results showed that lesion growth under estrus synchronization by ovariectomy with estrogen supplement had a higher success rate and more proliferative endometrium, apart from higher body weight gain. Immune responses in peripheral blood were similar in the whole uterus and solely endometrium fragments and in intraperitoneal injection and subcutaneous transplantation, but a more innate immune response in the peritoneal microenvironment was found in solely endometrium fragments and intraperitoneal injection than counterparts. In conclusion, different endometriosis modeling methods result in different pathological and immunological features. Ovariectomy with estrogen supplement, solely endometrium fragments, and intraperitoneal injection are more suitable for both pathological and immunological studies of endometriosis in mice, which are important for mechanistic studies and immunotherapy development.
Objective
To evaluate the impact of sex and menopausal status on the association between the epicardial adipose tissue (EAT) volume and diastolic function in patients with type 2 diabetes mellitus (T2DM).
Materials and Methods
A total of 542 consecutive patients with T2DM were retrospectively included in this study. All patients underwent cardiac computed tomographic as well as echocardiography. To assess the independent association of EAT and diastolic function parameters, we performed a multivariate linear regression analysis.
Results
The median EAT volume was 113.11 cm³ (interquartile range (IQR): 88.38, 148.03), and EAT volume was higher in men than in women (p < 0.05). We also discovered that EAT volume was significantly associated with diastolic function in both sexes after adjusting for risk factors (p < 0.05). Concerning menopausal status, EAT volume was higher in postmenopausal women than premenopausal women and was independently associated with the diastolic function only in postmenopausal women.
Conclusion
In patients with T2DM, EAT is independently associated with diastolic function in the male population and a portion of the female population. In contrast to premenopausal women, EAT volume is only significantly correlated with diastolic function in postmenopausal women.
Menopause results from the senescent reduction in ovarian follicular quantity and quality, which ultimately leads to the permanent cessation of menses and significant physiological and potential psychosocial consequences for women. The deficiency of estrogen that occurs in the postmenopausal state may cause a myriad of bothersome symptoms, in addition to increasing the risk of several chronic conditions, such as cardiovascular disease. This is especially true when menopause occurs early (< 45 years old). The gold standard of treatment for systemic menopausal symptoms and to mitigate the consequences of early estrogen loss in women is hormone therapy (HT). Several decades of research have shown that the benefits of HT use outweigh the risks in women without contraindications under the age 60 and/or less than 10 years from menopause. Women without a uterus generally need estrogen-alone therapy, while women with a uterus (i.e., endometrium) need estrogen-progestogen HT.KeywordsMenopausePerimenopauseHormone therapyHormone replacement therapyEstrogenFollicle-stimulating hormonePremature ovarian insufficiencyHot flashesVasomotor symptomsGenitourinary syndrome of menopauseWomen’s Health Initiative
Introduction:
This population-based cross-sectional study aimed to identify the best predictor of the 10-year cardiovascular (CV) high risk among old and new anthropometric indices.
Methods:
We investigated 76,915 adults older than 18 years of age living in southwest China. Ten obesity indices were calculated. The 10-year cardiovascular disease (CVD) risk was estimated using the Framingham risk score. Receiver operating characteristic curve analysis was performed to assess the ability of the anthropometric index to predict the 10-year high risk of CVD events.
Results:
The waist-to-hip ratio (WHR) had the highest area under the curve (AUC) value (0.711; sensitivity: 62.22%, specificity: 42.73%) in men, while the body fat index (BAI) had the lowest AUC value (0.624, sensitivity: 49.07%, specificity: 54.84%). The waist-to-height ratio (WHtR) and the body roundness index (BRI) showed the highest AUC value (0.751, sensitivity: 39.24%, 39.83%, specificity: 75.68%, 68.59%) in women, while the BAI showed the lowest AUC value (0.671, sensitivity: 53.15%, specificity: 57.14%).
Conclusions:
The WHR was the best anthropometric measure for assessing the 10-year high risk of CVD in men, while the WHtR and BRI were the best measures for women. In men, the WHR should be < 0.88, and in women, the WHtR should be < 0.502 or the BRI should be < 3.41.
Objective
A number of miRNAs and their targets were dragged in the differentiation of bone marrow mesenchymal stem cells (BMSCs). We aimed to elaborate the underlying molecular mechanisms of miRNA-320a in the osteoblast and adipocyte differentiation.
Methods
Trauma-induced osteonecrosis of the femoral head (TIONFH) and normal control samples (n = 10 for each group) were collected, followed by miRNA chip analysis to identify the differentially expressed miRNAs. H&E staining was used to observe the pathological development of TIONFH. Lentiviral vector was used for overexpression and inhibition of miRNA-320a in vitro. Quantitative real-time PCR (qPCR), Western blotting and immunohistochemistry staining were employed to determine the expression of interested genes at mRNA or protein level. Luciferase report assay was employed to determine the binding of miRNA-320a and RUNX2. Alkaline phosphatase (ALP) and Alizarin red staining were performed to observe the osteogenesis and Oil red O staining were conducted to visualize the adipogenesis.
Results
Expression of miRNA-320a was up-regulated while RUNX2 expression was down-regulated in TIONFH than Normal control. Luciferase report assay confirmed that miRNA-320a directly targeted to the 3′UTR of RUNX2. miRNA-320a overexpression significantly declined the expressions of osteogenesis-related markers: RUNX2, OSTERIX, Collagen I, Osteocalcin and Osteopontin. ALP and Alizarin red staining confirmed the inhibition function of miRNA-320a in osteogenesis of BMSCs. miRNA-320a inhibition significantly decreased the expression of adipogenesis-related markers: AP2, C/EBPα, FABP4 and PPARγ. Oil Red O staining confirmed the miRNA-320a inhibition reduced adipogenesis of BMSCs.
Conclusions
miRNA-320a inhibits osteoblast differentiation via targeting RUNX2 and promotes adipocyte differentiation of BMSCs.
Sex steroids, comprising of the androgens, estrogens, and progestogens, are fundamentally important to the development of muscle, bone, and fat across the life course. Each has roles that differ between these tissues, the male and female sexes, and developmental stage. It is the differential production of sex steroids and expression of their receptors that mediates much of the pubertal development in muscle, bone, and fat, which in turn determines the typical dimorphic sexual phenotypes. It is similar to how this differential production changes over time that is responsible for much of the typical sex-specific changes seen with normal aging.
This chapter considers the sex-specific production of sex steroids and their effects upon each muscle, bone, and fat. It additionally covers the developmental changes in sex steroid production, and how this contributes to age-related changes in these three tissues.
Osteosarcopenia is a growing healthcare challenge. This is compounded by a lack of pharmacological strategies to treat both muscle and bone simultaneously. While there are no approved medications for osteosarcopenia, there are some compounds that are known to have a dual role in the treatment of muscle and bone. This chapter discusses the relevant literature, the efficacy, and the challenges surrounding these agents, as well as identifying avenues of future research. Agents of the androgen and endocrine axes repurposed antifracture medications, and factors involved in the crosstalk in muscle and bone are discussed. While there are a number of promising opportunities for future research, as yet there is no clear front-runner in the race to a treatment. More research into the relationship between muscle and bone is required to identify key components of their intertwined physiologies in order to identify the critical factors and pathways that might regulate the disease.
With the rising prevalence of obesity, the incidence of type 2 diabetes mellitus (T2DM) has been steadily increasing globally over the last three decades. T2DM is characterized by elevated blood glucose levels associated with insulin resistance. Elevated blood glucose is associated with the formation of glycated hemoglobin (HbA1c) and other advanced glycation end products which may cause oxidative stress. Hyperglycemia leads to increased production of reactive oxygen species resulting in high levels of oxidative stress and inflammation. Evidence suggests that dietary interventions can improve diabetes outcomes. Soya (Glycine max L.) has been an important legume food crop for many millennia. The seed contains 30%–50% protein and 14%–24% unsaturated oil with considerable amount (>50%) of polyunsaturated fatty acids. In this chapter, we review some of the evidence linking soya intake, in particular soya protein and isoflavones, to glycaemic markers of T2DM from epidemiological and intervention trials, highlighting the importance of study design to the interpretation of results. We discuss potential mechanisms of action and the links to inflammation. We review strategies to integrate soya into functional foods for T2DM.
Purpose
We retrospectively analysed a cohort of patients treated at our Centre with bone marrow concentrated (BMC) injection for aneurysmal bone cyst (ABC) of the spine, in order to propose this treatment as a valid alternative for the management of ABCs.
Methods
Fourteen patients (6 male, 8 female) were treated between June 2014 to December 2019 with BMC injection for ABC of the spine. The mean age was 17.85 years. The mean follow up was 37.4 months (range 12- 60 months). The dimension of the cyst and the degree of ossification were measured by Computed Tomography (CT) scans before the treatment and during follow-up visits.
Results
Six patients received a single dose of BMC, five patients received two doses and in three patients three doses of BMC were administered. The mean ossification of the cyst (expressed in Hounsfield units) increased statistically from 43.48±2.36 HU to 161.71±23.48 HU during follow-up time and the ossification was associated to an improvement of the clinical outcomes. The mean ossification over time was significantly higher in patients treated with a single injection compared to patients treated with multiple injections. No significant difference in ossification was found between cervical and non-cervical localization of the cyst. Moreover, the initial size of the cyst was not statistically associated with the degree of ossification during follow-up
Conclusions
Results of this paper reinforce our previous evidence on the use of BMC as a valid alternative for spinal ABC management when SAE treatment is contraindicated or ineffective.
Pregnancy is a complex process requiring tremendous physiological changes in the mother in order to fulfill the needs of the growing fetus, and to give birth, expel the placenta and nurse the newborn. These physiological modifications are accompanied with psychological changes, as well as with variations in habits and behaviors. As a result, this period of life is considered as a sensitive window as impaired functional and physiological changes in the mother can have short- and long-term impacts on her health. In addition, dysregulation of the placenta and of mechanisms governing placentation have been linked to chronic diseases later-on in life for the fetus, in a concept known as the Developmental Origin of Health and Diseases (DOHaD). This concept stipulates that any change in the environment during the pre-conception and perinatal (in utero life and neonatal) period to puberty, can be “imprinted” in the organism, thereby impacting the health and risk of chronic diseases later in life. Pregnancy is a succession of events that is regulated, in large part, by hormones and growth factors. Therefore, small changes in hormonal balance can have important effects on both the mother and the developing fetus. An increasing number of studies demonstrate that exposure to endocrine disrupting compounds (EDCs) affect both the mother and the fetus giving rise to growing concerns surrounding these exposures. This review will give an overview of changes that happen during pregnancy with respect to the mother, the placenta, and the fetus, and of the current literature regarding the effects of EDCs during this specific sensitive window of exposure.
Introduction: Scientific data suggest that early exposure to endocrine-disrupting chemicals (EDCs) affect -repro, -neuro, -metabolic systems, to which are added other notions such as mixtures, window and duration of exposure, trans-generational effects, and epigenetic mechanisms.
Methods: In the present narrative review, we studied the relationship between exposure to EDCs with the appearance and development of obesity.
Results: Exposure to EDCs like Bisphenol A during the early stages of development has been shown to lead to weight gain and obesity. EDCs can interfere with endocrine signaling, affect adipocytes differentiation and endocrine function and disrupt metabolic processes, especially if exposure occurs at very low doses, in the mixture, during early development stages for several generations.
Conclusion: Exposure to EDCs is positively associated with obesity development. Moreover, the use of integrative approaches which mimicking environmental conditions are necessary and recommended to evaluate EDCs' effects in future studies.
Estrogen, a steroidal hormone has extensive biological activities and the effect is pleiotropic, affecting multiple systems in the body. Estrogens, the primary female sex hormones function to regulate the reproductive system by binding to specific receptors, the estrogen receptors (ERs). These ERs in turn control the expression of various genes by activating various transcriptional processes or signaling pathways. Given the importance of the role of estrogen in human physiology, they are also found to be involved in the development or control of several diseases which include but not limited to cancer, neurological disorders, obesity, gastrointestinal disorders, osteoporosis, cardiovascular diseases, inflammatory disease, etc. With support from many sophisticated studies, we provide insights on the importance of estrogen in human diseases. We reviewed here the role and the mechanisms of estrogen and its receptors that play a role in the development of severity in several diseases.
Genistein, an isoflavone in soybean products has potential cardio-protective effects and is used also as an alternative for estrogen therapy in postmenopausal women. However, results in this regard are inconsistent and also, not all risk factors related to cardiovascular supportive effects have been meta-analyzed. We searched PubMed, Scopus, ISI Web of Science, and Google Scholar from inception up to October 2020. Random-effects meta-analysis was used for data synthesis. The search included studies with information on genistein supplementation and BMI and body weight. Pooled results of studies showed that genistein intake significantly reduced TC [95%CI: -0.49(-0.80, -0.18); P=0.002)], LDL-C [95%CI: -0.60(-1.10, -0.10); P=0.018)] and SBP [95%CI: -0.52(-0.90, -0.14); P=0.007)]. DBP, HLD-C, TG, BMI, and body weight showed no meaningful improvement. Subgroup analysis showed that LDL-C and SBP were reduced more effectively in postmenopausal women with metabolic syndrome. Genistein intake more than 6 months showed a greater effect on lowering cholesterol -0.76(-1.27, -0.24), SBP [-0.39(-0.70, -0.08)] and DBP -0.40(-0.81, -0.00) and increasing TG and LDL-C. This meta-analysis provides consistent evidence that genistein intake reduces the CVD risk factors of TC, LDL-C, and SBP significantly.
The hypothalamus is a vital and an integral part of the central nervous system as it regulates a wide range of physiological and psychological processes, including energy homeostasis, reproduction, circadian rhythms, as well as emotional and behavioral patterns. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of an array of unique neuronal cell types that express critical neuromodulators required to mediate hypothalamic function. Until recently, the properties of these hypothalamic neurons were challenging to study, primarily because of the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus. However, hypothalamic neuronal cell models have proved to be a useful in vitro tool in understanding hypothalamic function and disorders. This chapter discusses the hypothalamic cell models that have been generated to date primarily to study mechanisms underlying the function of individual hypothalamic neurons in order to gain a more complete understanding of the overall physiology and pathology of the hypothalamus.
Previous studies have reported metals exposure contribute to the change of fasting blood glucose (FBG) level. However, the roles of reproductive hormones in their associations have not been fully elucidated. The aim of the study is to investigate the associations of multiple serum metals with reproductive hormones, and to further explore potential roles of reproductive hormones in relationships between metals exposure and FBG level. A total of 1911 Chinese Han men were analyzed by a cross-sectional study. We measured serum levels of 22 metals by inductively coupled plasma mass spectrometer (ICP-MS). FBG, total testosterone (TT), estradiol (E2), follicle stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) levels were determined. Least absolute shrinkage and selection operator (LASSO) regression models were conducted to select important metals, and restricted cubic spline models were then used to estimate dose-response relationships between selected metals and reproductive hormones. We also conducted mediation analyses to evaluate whether reproductive hormones played mediating roles in the associations between metals and FBG. We found significant inverse dose-dependent trends of copper, tin and zinc with E2; zinc with SHBG; copper and nickel with TT, while significant positive dose-dependent trend of iron with E2, respectively. Moreover, approximately inverted U-shaped associations existed between lead and SHBG, iron and TT. In addition, E2, SHBG and TT were negatively associated with FBG level. In mediation analyses, the association of copper with FBG was mediated by E2 and TT, with a mediation ratio of 10.4% and 22.1%, respectively. Furthermore, E2 and SHBG mediated the relationship of zinc with FBG, with a mediation ratio of 7.8% and 14.5%, respectively. E2 mediated 11.5% of positive relationship between tin with FBG. Our study suggested that the associations of metals exposure with FBG may be mediated by reproductive hormones.
Objective
Although the ovaries produce the majority of estrogens in women before menopause, estrogen is also synthesized in peripheral tissues such as adipose tissue (AT). The typical female AT distribution, concentrated in subcutaneous and femoro-gluteal regions, is estrogen-mediated, but the significance of estrogen synthesis in AT of premenopausal women is poorly understood.
Design and Methods
Serum and subcutaneous and visceral AT homogenates from 28 premenopausal women undergoing non-malignant surgery were analyzed for estrone, estradiol, and serum estrone sulfate (E1S) concentrations with liquid chromatography-tandem mass spectrometry. Isotopic precursors were used to measure enzyme activities of estrone-producing steroid sulfatase and estradiol-producing 17β-hydroxysteroid dehydrogenases (17β-HSD). Messenger RNA (mRNA) expression levels of genes for estrogen-metabolizing enzymes were analyzed using real-time reverse transcription quantitative polymerase chain reaction.
Results
While estradiol was the predominant circulating active estrogen, estrone dominated in AT, with a higher concentration in visceral than subcutaneous AT (median, 2657 vs 1459 pmol/kg; P = 0.002). Both AT depots converted circulating E1S to estrone, and estrone to estradiol. Median levels of estrone were five to ten times higher in subcutaneous and visceral AT than in serum (P < 0.001) and the estradiol level in visceral AT was 1.3 times higher than in serum (P < 0.005). The local estrone concentration in visceral AT correlated positively with mRNA expression of estrone-producing enzyme aromatase (r = 0.65, P = 0.003). Waist circumference correlated positively with increased estradiol production in subcutaneous AT (r = 0.60, P = 0.039).
Conclusions
Premenopausal AT demonstrated high estrogenic enzyme activity and considerable local estrogen concentrations. This may be a factor promoting female-typical AT distribution in premenopausal women.
We investigated sex- and menopause-related differences in body composition and regional fat distribution, using dual-energy X-ray absorptiometry (DEXA) in nonobese healthy volunteers. Men (n = 103) had a 50% greater lean tissue mass (P < 0.001) but a 13% lower fat mass (P < 0.001) than the women (n = 131). Postmenopausal (n = 70) women had a 20% greater fat mass (P < 0.001) than premenopausal (n = 61) women. The proportion of android (upper body) fat was greatest in men (48.6%, P < 0.001) but was significantly lower in premenopausal (38.3%) than in postmenopausal (42.1%) women (P < 0.001). The reverse was found for gynoid (lower body) fat (P < 0.001 ). DEXA measurements thus clearly demonstrated that sex differences in total fat mass were opposite those of android fat, and that marked menopausal changes in fat mass and its distribution existed. Body mass indices did not demonstrate that men had less total fat than women whereas postmenopausal women had more total fat than did premenopausal women. Our findings suggest that DEXA measurements of fat distribution may be useful for studies related to obesity-associated disease risk.
Estrogen exerts a variety of effects not only on female reproductive organs but also on nonreproductive organs, including
adipose tissue. Estrogen inhibits obesity triggered by ovariectomy in rodents. We studied the mechanism underlying this estrogen-dependent
inhibition of obesity. Estrogen markedly decreased the amounts of fat accumulation and lipoprotein lipase (LPL) mRNA as well
as triglyceride accumulation in genetically manipulated 3T3-L1 adipocytes stably expressing the estrogen receptor (ER). A
pLPL(1980)-CAT construct, along with an ER expression vector, was introduced into differentiated 3T3-L1 cells, and CAT activities
were determined. ER, mostly ligand-dependently, inhibited the basal LPL promoter activity by 7-fold. We searched the LPL promoter
for an estrogen-responsive suppressive element by employing a set of 5′-deletion mutants of the pLPL-CAT reporter. Although
there was no classical estrogen response element, it was demonstrated that an AP-1-like TGAATTC sequence located at (−1856/−1850)
was responsible for the suppression of the LPL gene transcription by estrogen. An electrophoretic mobility shift assay probed
with the TGAATTC sequence demonstrated formation of a specific DNA-nuclear protein complex. Interestingly, this complex was
not affected by the addition of any antibodies against ER, c-Jun, c-Fos, JunB, or JunD. Because this TGAATTC element responded
to phorbol ester and overexpression of CREB-binding protein abrogated the suppressive effect of estrogen on the LPL promoter,
we conclude that a unique protein that is related to the AP-1 transcription factor families may be involved in the complex
that binds to the TGAATTC element.
Context The prevalence of obesity and overweight increased in the United States
between 1978 and 1991. More recent reports have suggested continued increases
but are based on self-reported data.Objective To examine trends and prevalences of overweight (body mass index [BMI]
≥25) and obesity (BMI ≥30), using measured height and weight data.Design, Setting, and Participants Survey of 4115 adult men and women conducted in 1999 and 2000 as part
of the National Health and Nutrition Examination Survey (NHANES), a nationally
representative sample of the US population.Main Outcome Measure Age-adjusted prevalence of overweight, obesity, and extreme obesity
compared with prior surveys, and sex-, age-, and race/ethnicity–specific
estimates.Results The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared
with 22.9% in NHANES III (1988-1994; P<.001).
The prevalence of overweight also increased during this period from 55.9%
to 64.5% (P<.001). Extreme obesity (BMI ≥40)
also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant,
increases occurred for both men and women in all age groups and for non-Hispanic
whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did
not differ significantly in the prevalence of obesity or overweight for men.
Among women, obesity and overweight prevalences were highest among non-Hispanic
black women. More than half of non-Hispanic black women aged 40 years or older
were obese and more than 80% were overweight.Conclusions The increases in the prevalences of obesity and overweight previously
observed continued in 1999-2000. The potential health benefits from reduction
in overweight and obesity are of considerable public health importance.
Cortright, R. N., M. P. Chandler, P. W. R. Lemon and S. E. Dicarlo. Daily exercise reduces fat, protein and body mass in male but not female rats. Physiol Behav 62(1): 105–111, 1997.—This study was designed to compare the estimated energy balance, linear growth (body and bone lengths) and body composition (all components including body mass, total body water, fat, protein and ash) response to daily spontaneous running (DSR) in young male and female rats. We tested the hypothesis that due to gender differences in energy efficiency, DSR would reduce linear growth and body composition more in male rats. Fourteen male and sixteen female weanling Sprague-Dawley rats were randomly assigned to either a sedentary (SED) control (male 7, female 8) or DSR (male 7, female 8) group. The DSR rats were allowed to run spontaneously in running wheels while SED rats remained in standard rat cages for 9 weeks. Body mass, running distance and food intake were measured over the nine week period. Subsequently, chemical analysis was performed to measure carcass content of water, protein, fat and ash. Linear growth was assessed by measures of body and bone lengths. The estimated energy balance of the DSR rats was computed and compared between genders. Estimated energy balance was significantly more negative in females than males due to significantly greater DSR distance. Body and bone lengths were similar among the SED and DSR female and SED and DSR male rats. However, whole body mass, fat mass and protein mass were significantly lower only in DSR males. These results demonstrate that DSR reduced body mass, body fat and protein mass in male rats but not in female rats despite a more negative estimated energy balance in female rats. These findings suggest that females are better protected from an energy deficit due to DSR. Possible mechanisms include gender-specific hormonal responses.
We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting from a novel homozygous inactivating mutation of the CYP19 (P450arom) gene. At first observation, continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient presented also a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. The analysis of the effects induced by the successive treatment with high doses of testosterone, alendronate, and estradiol allows further insight into the roles of androgens and estrogens on several metabolic functions. High doses of testosterone treatment resulted in a severe imbalance in the estradiol to testosterone ratio together with the occurrence of insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of two carotid plaques. Furthermore, the study confirms previous data concerning the key role of estrogens on male bone maturation, at least in part, and regulation of gonadotropin secretion. The biopsy of the testis showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. Thus, a possible role of estrogen in male reproductive function is suggested but without revealing a direct cause-effect relationship.
Data from this case provide new insights into the role of estrogens in glucose, lipid, and liver metabolism in men. This new case of aromatase deficiency confirms previous data on bone maturation and mineralization, and it reveals a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.
The prevalence of obesity increased in the United States between 1976-1980 and 1988-1994 and again between 1988-1994 and 1999-2000.
To examine trends in obesity from 1999 through 2008 and the current prevalence of obesity and overweight for 2007-2008.
Analysis of height and weight measurements from 5555 adult men and women aged 20 years or older obtained in 2007-2008 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. Data from the NHANES obtained in 2007-2008 were compared with results obtained from 1999 through 2006.
Estimates of the prevalence of overweight and obesity in adults. Overweight was defined as a body mass index (BMI) of 25.0 to 29.9. Obesity was defined as a BMI of 30.0 or higher.
In 2007-2008, the age-adjusted prevalence of obesity was 33.8% (95% confidence interval [CI], 31.6%-36.0%) overall, 32.2% (95% CI, 29.5%-35.0%) among men, and 35.5% (95% CI, 33.2%-37.7%) among women. The corresponding prevalence estimates for overweight and obesity combined (BMI > or = 25) were 68.0% (95% CI, 66.3%-69.8%), 72.3% (95% CI, 70.4%-74.1%), and 64.1% (95% CI, 61.3%-66.9%). Obesity prevalence varied by age group and by racial and ethnic group for both men and women. Over the 10-year period, obesity showed no significant trend among women (adjusted odds ratio [AOR] for 2007-2008 vs 1999-2000, 1.12 [95% CI, 0.89-1.32]). For men, there was a significant linear trend (AOR for 2007-2008 vs 1999-2000, 1.32 [95% CI, 1.12-1.58]); however, the 3 most recent data points did not differ significantly from each other.
In 2007-2008, the prevalence of obesity was 32.2% among adult men and 35.5% among adult women. The increases in the prevalence of obesity previously observed do not appear to be continuing at the same rate over the past 10 years, particularly for women and possibly for men.
For the first time, four well-characterized compounds from four distinct chemical classes were directly compared for efficacy and potency in hone, uteri, lipids, and adipose tissues in an ovariectomized model with 6 month old rats. Five weeks of oral dosing confirmed that ethynyl estradiol, tamoxifen, and raloxifene are potent inhibitors of the loss in volumetric bone mineral density (BMD, mg/cc) induced by ovariectomy, as measured by computed tomography. In the metaphysis of distal femora from ovariectomized rats, analysis showed a significant 12-20% decrease (P< 0.01) in the BMD. Linear regression analysis was used to calculate half-maximal efficacious doses for ethynyl estradiol ED(50) =0.04mg /kg, which was threefold more potent than tamoxifen, which in turn was threefold more potent than raloxifene, which was more efficacious than nafoxidine. In the uterus, raloxifene had minimal effects on the endometrium and smaller effects on uterine eosinophil peroxidase activity than nafoxidine, tamoxifen, or estrogen, respectively. Estrogen was the most potent in reducing cholesterol levels in ovariectomized rats, whereas tamoxifen and nafoxidine were more effective than raloxifene in blocking gain in body weight. Distinct compounds had advantages in the management of bone, uterine, serum cholesterol, and adipose tissues after ovariectomy. The distinct pattern of pharmacological effects may be best understood in terms of their respective chemical structure, specifically estrogens, benzothiophenes (raloxifene), dihydronapthylenes (nafoxidine), and triphenylethylenes (tamoxifen). These data point to advantages of separate compounds in the management of bone, uterine, serum cholesterol, and adipose tissues after estrogen deficiency, and show that the benzothiophene raloxifene has potentially important advantages over estrogen, tamoxifen, or nafoxidine in the uterus.
Molecular mechanisms coupling growth arrest and cell differentiation were examined during adipogenesis. Data are presented that document a cascade expression of members of two independent families of cyclin-dependent kinase inhibitors that define distinct states of growth arrest during 3T3-L1 preadipocyte differentiation. Exit from the cell cycle into a pre-differentiation state of post-mitotic growth arrest was characterized by significant increases in p21 and p27. During onset of irreversible growth arrest associated with terminal differentiation, the level of p21 declined with a concomitant, dramatic increase in p18 and a sustained level of p27. The expression of p18 and p21, regulated at the level of protein and mRNA accumulation, was directly coupled to differentiation. Stable cell lines were engineered to express adipogenic transcription factors to examine the active role of trans-acting elements in regulating these cell cycle inhibitors. Ectopic expression of peroxisome proliferator-activated receptor (PPAR) gamma in non-precursor fibroblastic cell lines resulted in conversion to adipocytes and a coordinated increase in p18 and p21 mRNA and protein expression in a PPARgamma ligand-associated manner. These data demonstrate a role for PPARgamma in mediating the differentiation-dependent cascade expression of cyclin-dependent kinase inhibitors, thereby providing a molecular mechanism coupling growth arrest and adipocyte differentiation.
All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn. Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses. Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not. Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product. As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted. Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms. As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems. The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well. As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male. The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type. The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO. In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes. The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising. In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus. [ABSTRACT TRUNCATED]
To investigate the role of sex steroid hormones in adipose tissue development and distribution, we have studied the effect of various sex steroids (testosterone, dihydrotestosterone (DHT), and 17beta-estradiol) in vitro, on the proliferation and differentiation processes in rat preadipocytes from deep (epididymal and parametrial) and superficial (femoral sc) fat deposits. All added steroids failed to affect the growth rate of preadipocytes from male rats when determined from day 1 to day 4 after plating, whether FCS was present or not in the culture medium. In contrast, in preadipocytes from female rats, we observed a positive effect (x2) of 17beta-estradiol (0.01 microM) on the proliferative capacities of sc but not parametrial preadipocytes. When preadipocytes were exposed to testosterone or DHT (0.1 microM) during the differentiation process, the glycerol 3-phosphate dehydrogenase activity was significantly decreased in epididymal preadipocytes only. When preadipocytes from male rats were exposed to 17beta-estradiol (0.01 microM), the differentiation capacities of preadipocytes were not modified. However, in parametrial preadipocytes from ovariectomized female rats, 17beta-estradiol significantly increased (x1.34) the glycerol 3-phosphate dehydrogenase activity. In differentiated preadipocytes that had been exposed to sex steroids, expression of peroxisome proliferator-activated receptor gamma2 was up-regulated by 17beta-estradiol but not by androgens. As described in other cell types, sex steroids modulate insulin growth factor 1 receptor (IGF1R) expression in preadipocytes. Indeed, IGF1R levels were either enhanced by 17 beta-estradiol (0.01 microM) in sc preadipocytes from female ovariectomized rats or decreased by DHT (0.01 microM) in epididymal preadipocytes. These effects were reversed by simultaneous exposure to androgen or estrogen receptor antagonists. In conclusion, this study demonstrates that, in rat preadipocytes kept in primary culture and chronically exposed to sex hormones, androgens elicit an antiadipogenic effect, whereas estrogens behave as proadipogenic hormones. Moreover, our results suggest that these opposite effects could be related to changes in IGF1R (androgens and estrogens) and peroxisome proliferator-activated receptor gamma2 expression (estrogens).
Estrogen exerts a wide variety of actions involving many target tissues. We studied the effects of long-term ovariectomy (OVX) and OVX with 17beta-estradiol treatment (OVXE2) on the level of estrogen receptor (ER) gene expression in target tissues of female rats.
Three groups of Sprague-Dawley female rats were utilized in this study: sham operated (SO), OVX and OVXE2.
SO and OVX were performed 2 weeks before starting the 17beta-estradiol treatment. All groups were maintained on liquid diet for 12 weeks from the time of estradiol treatment. Total RNA was prepared from the tissues of the rats and relative quantitative reverse transcription PCR was utilized to compare the ER alpha-subtype (ERalpha) mRNA level in the three groups for each target tissue.
Following long-term OVX, the levels of ERalpha expression showed a significant increase in the uterus, kidney and cerebral cortex and no significant change in the liver, cerebellum, brainstem, heart and thoracic and abdominal aorta compared with their SO levels. On the other hand, a 12-week treatment of OVX rats with 17beta-estradiol restored the previously upregulated ERalpha mRNA to near SO levels except for the liver where the 17beta-estradiol treatment resulted in a significant increase in the ERalpha mRNA level compared with that in SO rats.
We conclude that the regulation of ERs by its ligand is tissue specific.
The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.
Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous cycles, ovulatory defects, and atrophic uterus. The heterozygous animals that initially show reduced fertility undergo early reproductive senescence and stop breeding altogether. Lack of FSH-R signaling in females causes severe ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase gene transcription and translation are unaltered in the mutants. Early loss of estrogen in the null mutants leads to obesity and skeletal abnormalities that intensify with age producing (kyphosis), a hunchback appearance. Both these changes also become apparent in older heterozygous mice coincident with early reproductive senescence. The expression of nuclear estrogen receptor(s) alpha and beta genes and the corresponding proteins in the ovary and uterus of FORKO mice appear to be intact. The loss of ovarian estrogen creates an imbalance in A and B forms of the progesterone receptor in the uterus of both heterozygotes and null mutants. Some of the changes we have documented here in FORKO mice are reminiscent of the ovarian dysfunction and other major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17beta administration promptly induced uterine growth and reversed the accumulation of adipose tissue indicating that estrogen receptors are functional. Thus, the phenotypes evident in these genetically altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting.
Flavonoids, polyphenolic compounds that exist widely in plants, inhibit cell proliferation and increase cell differentiation in many cancerous and noncancerous cell lines. Because terminal differentiation of preadipocytes to adipocytes depends on proliferation of both pre- and postconfluent preadipocytes, we predicted that flavonoids would inhibit adipogenesis in the 3T3-L1 preadipocyte cell line. The flavonoids genistein and naringenin inhibited proliferation of preconfluent preadipocytes in a time- and dose-dependent manner. When added to 2-day postconfluent preadipocytes at the induction of differentiation, genistein inhibited mitotic clonal expansion, triglyceride accumulation, and peroxisome proliferator-activated receptor-gamma expression, but naringenin had no effect. The antiadipogenic effect of genistein was not due to inhibition of insulin receptor subtrate-1 tyrosine phosphorylation. When added 3 days after induction of differentiation, neither flavonoid inhibited differentiation. In fully differentiated adipocytes, genistein increased basal and epinephrine-induced lipolysis, but naringenin had no significant effects. These data demonstrate that genistein and naringenin, despite structural similarity, have differential effects on adipogenesis and adipocyte lipid metabolism.
In some tissues, rapid effects of estrogens have been described at the plasma membrane level including activation of the MAPK activity. In rat adipocytes, the present study demonstrates that physiological concentrations (0.1–10 nm) of E2 rapidly activate the p42/p44 MAPK. This effect was blocked by the pure estrogen antagonist, ICI 182 780, and appeared specific for E2 because 17α-E2, T, and progesterone failed to change the MAPK activity. Pertussis toxin; PP2, a selective inhibitor of Src family kinase; and wortmannin all reduced the magnitude of MAPK activation by E2 suggesting involvement of the Gi-protein/Src family kinase/PI3K pathway. Classical PKCs and MAPK kinase were also involved in MAPK activation by E2. Interestingly, this activation was observed in late but not early differentiated rat preadipocytes, and the immunoreactive ERα protein was detected only in adipocyte membrane, suggesting that the adipocyte membrane structure is required for the nongenomic effect of E2. Moreover, E2 induced a rapid nuclear translocation of MAPK together with a fast MAPK- dependent activation of cAMP response element binding protein leading to a transcriptional activation of cAMP response element binding protein-responsive genes and reported plasmids. However, the E2 increase in adipocyte activator protein-1 DNA binding does not seem to be fully explained by the E2 activation of the MAPK pathway. This study provides clear evidence for an additional nongenomic mechanism whereby estrogens may exert their control on adipose tissue metabolism.
To investigate the role of sex steroid hormones in adipose tissue development and distribution, we have studied the effect of various sex steroids (testosterone, dihydrotestosterone (DHT), and 17β-estradiol) in vitro, on the proliferation and differentiation processes in rat preadipocytes from deep (epididymal and parametrial) and superficial (femoral sc) fat deposits. All added steroids failed to affect the growth rate of preadipocytes from male rats when determined from day 1 to day 4 after plating, whether FCS was present or not in the culture medium. In contrast, in preadipocytes from female rats, we observed a positive effect (×2) of 17β-estradiol (0.01μ m) on the proliferative capacities of sc but not parametrial preadipocytes. When preadipocytes were exposed to testosterone or DHT (0.1 μm) during the differentiation process, the glycerol 3-phosphate dehydrogenase activity was significantly decreased in epididymal preadipocytes only. When preadipocytes from male rats were exposed to 17β-estradiol (0...
Clinical evidence suggests that sex hormones affect adipose tissue metabolism and deposition. To investigate the biosynthesis and possible action of estrogen in adipose tissue, we report the use of competitive, specific polymerase chain reaction amplifications to determine levels of estrogen receptor (ER) messenger RNA (mRNA) and cytochrome P450 aromatase mRNA in adipocytes and adipose stromal cells. This extremely sensitive technique uses coamplification of a homologous animal species complementary RNA to control for differences in amplification efficiencies. The DNA amplification products are identified by Southern hybridization with species-specific radiolabeled oligonucleotide probes. Abdominal adipose tissue obtained from female patients during elective abdominoplasty was separated by collagenase digestion and centrifugation into floating adipocytes and pelleted adipose stromal cells. Our results demonstrate higher ER mRNA levels in adipocytes compared to adipose stromal cells, whereas cytochrome P450 aromatase mRNA levels are higher in adipose stromal cells compared to adipocytes. The finding of ER mRNA in adipose tissue suggests the presence of the ER in adipose tissue. In addition the inverse correlation of ER mRNA and cytochrome P450 aromatase mRNA levels in adipocytes and adipose stromal cells suggests a paracrine relationship whereby estrogen produced by adipose stromal cells affects adjacent adipocytes.
The Cyclin D-Cdk4,6/INK4/Rb/E2F pathway plays a key role in controlling cell growth by integrating multiple mitogenic and antimitogenic stimuli. The components of this pathway are gene families with a high level of structural and functional redundancy and are expressed in an overlapping fashion in most tissues and cell types. Using classical transgenic technology as well as gene-targeting in ES cells, a series of mouse models have been developed to study the in vivo function of individual components of this pathway in both normal homeostasis and tumor development. These models have proven to be useful to define specific as well as redundant roles among members of these cell cycle regulatory gene families. This pathway is deregulated in the vast majority of human tumors by genetic and epigenetic alterations that target at least some of its key members such as Cyclin D1, Cdk4, INK4a and INK4b, pRb etc. As a consequence, some of these molecules are currently being considered as targets for cancer therapy, and several novel molecules, such as Cdk inhibitors, are under development as potential anti-cancer drugs.
Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous cycles, ovulatory defects, and atrophic uterus. The heterozygous animals that initially show reduced fertility undergo early reproductive senescence and stop breeding altogether. Lack of FSH-R signaling in females causes severe ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase gene transcription and translation are unaltered in the mutants. Early loss of estrogen in the null mutants leads to obesity and skeletal abnormalities that intensify with age producing (kyphosis), a hunchback appearance. Both these changes also become apparent in older heterozygous mice coincident with early reproductive senescence. The expression of nuclear estrogen receptor(s) α and β genes and the corresponding proteins in the ovary and uterus of FORKO mice appear to be intact. The loss of ovarian estrogen creates an imbalance in A and B forms of the progesterone receptor in the uterus of both heterozygotes and null mutants. Some of the changes we have documented here in FORKO mice are reminiscent of the ovarian dysfunction and other major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17β administration promptly induced uterine growth and reversed the accumulation of adipose tissue indicating that estrogen receptors are functional. Thus, the phenotypes evident in these genetically altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting.
We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granulosa cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta -estradiol (E2) with high affinity (Kd = 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha -androstane-3beta ,17beta -diol >> testosterone = progesterone = corticosterone = 5alpha -androstane-3alpha ,17beta -diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha -androstane-3alpha ,17beta -diol could stimulate reporter gene activity, whereas estrone and 5alpha -androstane-3beta ,17beta -diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha ) from rat uterus.
Although cells of the osteoblast lineage express functional ERs, direct effects of estrogen on bone formation remain ob- scure. In the present study, we have investigated estrogen effects on osteoblastic and adipocytic differentiation from a mouse bone marrow stromal cell line, ST-2, which had been manipulated to overexpress either human ER (ST2ER )o r ER (ST2ER). Treatment with bone morphogenetic protein-2 increased alkaline phosphatase activity as well as the number of Oil Red O-positive adipocytes, indicating that bone mor- phogenetic protein-2 stimulated both osteoblastic and adipo- cytic differentiation from these bipotential cells. In both ST2ER and ST2ER cells, cotreatment with E2 caused en- hancement of alkaline phosphatase activity and suppression of lipid accumulation. These effects were completely reversed by an ER antagonist, ICI182780. Therefore, the estrogen reg- ulation occurred in an ER-specific manner but without ER subtype specificity. Moreover, dose response curves of the opposing effects of estrogen on osteoblastogenesis and adi- pogenesis formed an apparent mirror image, consistent with a reciprocal regulation of differentiation into the two cell lineages. These results demonstrate that estrogen directly modulates differentiation of bipotential stromal cells into the osteoblast and adipocyte lineages, causing a lineage shift to- ward the osteoblast. Such effects would lead to direct stimu- lation of bone formation and thereby contribute to the pro- tective effects of estrogen on bone. (Endocrinology 143: 2349 -2356, 2002)
Ovarian and testicular steroids have important effects on body weight and composition in rats. Estradiol and testosterone decrease adiposity, while progesterone increases carcass fat content. These hormone-induced changes in body weight and composition are accompanied by changes in food intake and voluntary exercise, suggesting that the hormones induce behavioral changes which alter body weight and adiposity. However, several lines of evidence indicate that these behavioral changes are neither necessary nor sufficient to produce the hormone-induced body weight shifts. Rather, peripheral metabolic effects of gonadal steroids may be of primary importance in the control of fat disposition. Steroid effects on triglyceride clearance from circulation, along with changes in hepatic synthesis, may in turn alter the availability of triglycerides as an oxidizable fuel, contributing to the changes in food intake. From this perspective, estradiol- and progesterone-induced changes in food intake are viewed as consequences, rather than causes, of changes in fat metabolism. It is suggested that during naturally-occurring reproductive states gonadal steroids interact with other hormones, such as prolactin, to partition available triglycerides among tissues which oxidize, excrete or store long-chain fatty acids (e.g., striated muscle, mammary gland, or adipose tissue, respectively).
Body cell mass, body fat, and total number of fat cells were determined in young men and women. In addition, regional determinations of adipose tissue thickness, fat cell size, and fat cell number were also performed. The individuals studied were 11 male and 12 female medical students with a mean age of 22 yr. In order to avoid deviations from ideal body weights, the individuals were preselected by using anthropometric standards. The women had more body fat than the men, which was due to an increase in the total number of fat cells. Mean fat cell size did not differ significantly between sexes. The women had greater adipose tissue thickness than the men, which was primarily due to an increase in local fat cell number in all regions investigated (epigastric, hypogastric, femoral, and gluteal) except in the gluteal region, where the difference was mainly explained by larger fat cells in women. When expressed in per cent of maximum values, the intrasexual patterns of adipose tissue thickness and local fat cell number in different regions were similar in men and women, while the pattern concerning fat cell size was slightly different between the sexes. There were no differences between sexes in cholesterol, triglyceride, fasting blood sugar, or fasting insulin values. Middle-aged randomly selected men and women examined previously had a larger amount of body fat than the young men and women, respectively, examined in the present investigation. This difference in body fat with age was due to a larger mean fat cell size in the middle-aged populations, while there was no difference in total fat cell number.
The influence of 17beta-estradiol and 17alpha-estradiol on adult human omental adipocyte precursors grown in a propagating culture system was studied. Cells were grown in subculture in the presence or absence of hormone. 17beta-estradiol resulted in significant promotion of adipocyte precursor replication, as determined by cell counting and incorporation of radioactive thymidine into DNA. The hormone stimulated cell multiplication in the concentration range 0.5--500 ng/ml growth medium. The highest level tested was 500 ng/ml. The maximal effects were obtained at 50 ng/ml (P less than 0.001 by paired t test, 48 h after hormone addition). All 10 cell strains (five were derived from men and five from women) that were tested responded similarly to the hormone. 17beta-estradiol did not affect cell size. 17alpha-estradiol did not promote the replication of adipocyte precursors, nor did it influence cell size. Thus, 17beta-estradiol, which is the active isomer in known target tissues, stimulates the multiplication of human adipocyte precursors in culture.
The effect of 17beta-estradiol or progesterone administration on adipose tissue lipoprotein lipase activity was studied in male and ovariectomized female rats. Lipoprotein lipase activity was measured in acetone-ether-extracted preparations of adipose tissue with doubly labeled (14C-fatty acid, 3H-glyceryl) chylomicron triglyceride as substrate. Administration of 17beta-estradiol to male rats lowered adipose tissue lipoprotein lipase activity from 8.22 plus or minus 1.8 U/g (1 U = 1 mumol triglyceride hydrolyzed per h) to 4.96 plus or minus 0.5 U/g in the treated group. Ovariectomy increased adipose tissue lipoprotein lipase activity from 10.4 plus or minus 1.8 U/g in controls to 22.7 plus or minus 4.3 U/g. 17beta-Estradiol administration to ovariectomized rats cuased a marked fall in adipose tissue lipoprotein lipase activity: 17beta-estradiol (2.5 mug/day) lowered the enzyme activity to 9.00 plus or minus 1.2 U/g, whereas 25 mug/day further decreased lipoprotein lipase activity to 3.2 plus or minus 0.6 U/g. Blood triglyceride levels increased from 0.8 plus or minus 0.05 mumol/ml in ovariectomized rats to 1.4 plus or minus 0.09 mumol/ml in 25 mug/day 17beta-estradiol-treated rats. Progesterone administration did not affect adipose tissue lipoprotein lipase activity in either male or ovariectomized rats. Heart and lung lipoprotein lipase activity was unaffected by hormone treatment. We suggest that the rise in blood triglyceride concentrations, which accompanies high palsma estrogen levels, could be due to the marked inhibition of adipose tissue lipoprotein lipase activity.
We investigated sex- and menopause-related differences in body composition and regional fat distribution, using dual-energy X-ray absorptiometry (DEXA) in nonobese healthy volunteers. Men (n = 103) had a 50% greater lean tissue mass (P less than 0.001) but a 13% lower fat mass (P less than 0.001) than the women (n = 131). Postmenopausal (n = 70) women had a 20% greater fat mass (P less than 0.001) than premenopausal (n = 61) women. The proportion of android (upper body) fat was greatest in men (48.6%, P less than 0.001) but was significantly lower in premenopausal (38.3%) than in postmenopausal (42.1%) women (P less than 0.001). The reverse was found for gynoid (lower body) fat (P less than 0.001). DEXA measurements thus clearly demonstrated that sex differences in total fat mass were opposite those of android fat, and that marked menopausal changes in fat mass and its distribution existed. Body mass indices did not demonstrate that men had less total fat than women whereas postmenopausal women had more total fat than did premenopausal women. Our findings suggest that DEXA measurements of fat distribution may be useful for studies related to obesity-associated disease risk.
The nuclear estrogen receptor was characterised in isolated rat adipocytes. The binding reaction with [3H]estradiol was performed with intact isolated rat adipocytes and the radioactivity associated with the nucleus was subsequently determined after cell lysis. The nuclear uptake of [3H]estrogen in rat adipocytes was temperature dependent and steroid specific. The steady-state binding was achieved after 30 min at 37 degrees C and was constant for several hours. Estradiol was found to bind to a homogeneous class of nuclear receptors in epididymal adipocytes with an apparent Kd of 3.1 +/- 0.76 nM and a Bmax of 7.98 +/- 1.11 fmol/10(6) cells corresponding to about 4800 receptors per nucleus. The estradiol binding exhibited regional variations in isolated adipocytes. In lean rats the highest receptor number was found in epididymal adipocytes, whereas there was a significantly lower number of nuclear binding sites in perirenal and subcutaneous adipocytes (P less than 0.05), unlike in older and more obese rats where the nuclear estradiol binding was greatest in adipocytes from the perirenal fat depot. Incubations with isoproterenol (10 microM) and dibutyryl-cAMP (2.5 mM) both reduced estradiol binding by 56% (P less than 0.005), while insulin (1 nM) enhanced the estradiol binding by 37% (P less than 0.01). In conclusion, a specific and high affinity nuclear estradiol receptor was demonstrated in rat adipocytes and regional differences in nuclear estradiol binding were detected. Furthermore, it was demonstrated that nuclear estradiol binding could be modulated by other agents known to affect adipocyte metabolism.
Adipose tissue distribution in man is dependent on genetic and environmental factors. The total and regional masses of adipose tissue are dependent on the number of adipocytes as well as their degree of filling with depot fat. Currently available evidence does not suggest a specific regional regulation of fat cell multiplication in subcutaneous depots, which instead seems to occur at a certain critical degree of filling of available adipocytes. The control of the rate of filling of adipocytes then seems to be the main factor determining the local, regional mass of adipose tissue. This in turn is regulated by the balance between the lipid accumulating and mobilization processes. The steroid hormones exert major permissive effects on these processes. It seems likely that the resulting effect of the rate of secretion of various steroid hormones, and the local density of their specific receptors, decide the regional distribution of body fat. Physiological and clinical situations with defined differences in these regulatory factors would then be expected to have characteristically different adipose tissue distribution. Sex differences include a larger subcutaneous adipose tissue in women than men, explainable at least partly by a depot in the gluteal-femoral region in women, which is essentially absent in non-obese men. Men on the other hand seem to have a larger proportion of their adipose tissue organ localized intra-abdominally. In addition, the gluteal-femoral fat cells are specifically enlarged in women, and have a higher lipoprotein lipase activity. While the larger adipose tissue in non-obese women may well be genetically linked, the specific characteristics of the gluteal-femoral adipocytes are most likely regulated by female sex steroid hormones. Another apparent sex difference is the ability of women to protect visceral depots from fat accumulation up to a certain degree of obesity, while men deposit excess fat in this region in parallel with other depots. This might, at least partly, simply be explainable by the smaller 'available space' in male than female adipose tissue. It should be emphasized that the effects of sex steroid hormones on the regulation of adipocyte metabolism occur only in concert with cortisol, which is always present. Cortisol itself expresses lipoprotein lipase activity as well as beta-adrenergic receptors (BARs), and probably has additional effects, not yet revealed. The net effect seems, however, to be lipid accumulation as seen in the apparently glucocorticoid receptor (GR) dense visceral adipose tissue in conditions of glucocorticoid excess, such as Cushing's syndrome. The effects of the sex steroid hormones should be regarded against this background.(ABSTRACT TRUNCATED AT 400 WORDS)
The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P less than .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P less than .001), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat.
The presence of receptors for oestradiol-17 beta and 5 alpha-dihydrotestosterone (5 alpha-DHT) in the human monocytic leukaemia cell line J111 and rat peritoneal macrophages was investigated using whole-cell assays. For both cell types, high-affinity binding species for oestrogen were detected, whereas no indication of specific binding was observed for 5 alpha-DHT. Analysis of the data according to Scatchard showed curved lines, indicating the presence of two different oestrogen-binding species. The dissociation constant (Kd) values for the receptors of the rat peritoneal macrophages were calculated to be 1.4 x 10(-10) M and 3.3 x 10(-9) M, while for the J111 cells, the Kd values were 8.7 x 10(-11) M and 2.5 x 10(-9) M. Sucrose-gradient ultracentrifugation identified one oestrogen-binding species of 7.1S. The receptors had a relatively high affinity for diethylstilboestrol (DES) but did not bind to a monoclonal antibody specific for the classical oestrogen receptor, suggesting that oestrogen receptors in macrophages could be of a different type.
We examined the effects of insulin on glucose transport and subcellular glucose transporter distribution in isolated omental adipose cells from men and women. 3-O-Methylglucose transport was measured in intact cells, and the number of glucose transporters in plasma membranes and low density microsomal membranes was determined using the cytochalasin B binding assay. Compared to adipocytes from women, omental adipocytes from men were characterized by 1) 2-fold larger cell volume; 2) 4- to 5- and 2.5-fold higher glucose transport rates when calculated per cell or per cell surface area, respectively, in either basal or insulin-stimulated cells; 3) similar 2-fold insulin stimulating effect per se; and 4) equal concentrations of transporters in both fractions examined, but a 2-fold increase in their total number per cell. Additionally, although not directly measured, the calculated glucose transporter activity in basal plasma membranes prepared from adipocytes from men was 2.7-fold higher than that in women, and insulin further induced a 30% increase in that activity. Thus, a sex-related difference was found between the number of glucose transporters per cell and the resultant glucose transport activity of the intact cells. Together with the increased specific activity of glucose transporters in men compared to women, our findings indicate a sex-related difference in adipocyte glucose transport, mainly due to an increase in the number and modulation of the intrinsic activity of glucose transporters in the plasma membrane.
Gonadal steroids affect energy balance and adiposity in a variety of mammalian species. For example, estradiol acts via multiple, redundant mechanisms to reduce body weight and adiposity. The steroid can act directly in the brain to decrease food intake and stimulate voluntary exercise. Sex hormones may act concurrently in non-neural peripheral tissues to alter metabolic processes and energy balance. White adipose tissue estrogen receptors may mediate estradiol-induced decreases in lipoprotein lipase activity and lipid storage. Finally, estradiol increases energy expenditure independent of any effects on voluntary exercise. Brown adipose tissue is a potential site for estradiol-induced thermogenesis.
The role of catechol estrogens or methoxy derivatives of these compounds in the regulation of lipolysis was evaluated using adipocytes prepared from rat epididymal fat pads. Glycerol released into the incubation medium was measured as ab index of lipolysis. When adipocytes were incubated with epinephrine alone (5 x 10-7 M), glycerol formation was increased 2- to 5-fold over that in untreated cells. Incubation of cells in the presence of 2-hydroxyestrone, 2-hydroxyestradiol, 2-methoxyestrone, 2-methoxyestradiol, estrone, or 17β-estradiol did not increase triglyceride hydrolysis over that in untreated cells. However, when cells were incubated with epinephrine together with either 2-hydroxyestrone, 2-hydroxyestradiol, or 2-methoxyestradiol glycerol formation was increased 2- to 3-fold over the rate in cells treated with epinephrine alone. Estrone 17β-estradiol, and 2-methoxyestradiol did not affect the rate of epinephrine-induced lipolysis in adipocytes. To define whether catechol estrogens were potentiating the lipolytic effect of epinephrine by competition for catechol-O-methyltransferase (COMT), adipocytes were incubated with epinephrine in the presence of a number of COMT inhibitors. Each of these COMT inhibitors potentiated the lipolytic effect of epinephrine, but did not potentiate further the stimulatory effect of catechol estrogens on epinephrine-induced lipolysis. 2-Hydroxyestrone, 2-hydroxyestradiol, or 2-methoxyestradiol did not potentiate the lipolytic effect of soterenol, a β-adrenergic agonist that is not a substrate for COMT. The steroids that potentiated the epinephrine-induced lipolytic response also inhibited the formation of [3H]methanephrine from [3H]epinephrine in rat adipocytes. These data suggest that catechol estrogens compete with epinephrine for binding to COMT and thereby enhance the lypolytic effect of epinephrine.
Measures of adipocyte size and body density were collected from 217 nonobese adults 20 to 50 yr of age, and estimates of total body fat, percentage body fat, and adipocyte number were calculated. Women had a greater percentage body fat than men in every age group except the oldest. Women had significantly greater amounts of total body fat and larger adipocytes than men in the 20- to 24-yr group, but men had significantly greater amounts of total body fat than the women in the 45- to 50-yr group. Adipocyte number, total body fat, and percentage body fat are each positively correlated with age in both sexes. Adipocyte size is not correlated with age but is positively correlated with total and percent body fat in men and women irrespective of age. These cross-sectional data suggest that adipocyte number, rather than being stable during adulthood, increases with age and is associated with corresponding increases in total and percentage body fat.
In 111 boys and girls, 10 to 18 yr of age, body density was measured by underwater weighing, and the size of adipocytes in adipose tissue from the buttocks was measured by the osmium tetroxide method. From these two measures, estimates of percentage body fat, total body fat, and adipocyte number were computed for most of the children. Their skeletal age was also calculated by an acceptable method. Across chronological age, the girls have significantly larger mean values of total and percentage body fat and larger and more numerous adipocytes than the boys. The mean number of adipocytes in each sex is within adult levels, as is the mean size of the adipocytes in the girls. The boys' mean adipocyte size is below the adult level. There are negative, significant correlations between percentage body fat and chronological or skeletal age in the boys, and positive significant correlations between total body fat and chronological or skeletal age in the girls. Also, adipocyte size is positively correlated with percentage body fat but only in the boys. With the effects of chronological age removed, percentage body fat was significantly and negatively correlated with skeletal age in boys only. All other correlations among the variables were not statistically significant.
Cell culture models (e.g. 3T3-L1 cells) have been developed for studying the process of adipocyte differentiation. Differentiation can be induced by adding insulin-like growth factor I, glucocorticoid, fatty acids, and an agent that increases intracellular cAMP level. The adipocyte differentiation program is regulated by transcriptional activators such as CCAAT/enhancer binding protein alpha (C/EBP alpha), peroxisomal proliferator activated receptor gamma 2 (PPAR gamma 2), fatty acid activated receptor (FAAR), and transcriptional repressors such as preadipocyte repressor element binding protein (PRE) and C/EBP undifferentiated protein (CUP). These transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype including the insulin-responsive glucose transporter (GLUT4), stearoyl CoA desaturase 1 (SCD1), and the fatty acid binding protein (422/aP2).
Human airway epithelial cell lines that retain phenotypic properties representative of the native tissue will be useful physiological models. Human papilloma viral (HPV) genes can immortalize human genital keratinocytes and breast and bronchial epithelia. We transfected cystic fibrosis (CF) and normal tracheobronchial epithelial cell cultures with DNA encoding the HPV-18 E6 and E7 genes and characterized phenotypic properties of resultant cell lines. Of the 11 CF clones isolated, 6 developed a polarized phenotype with vectorial ion transport and membrane-specific expression of histamine and purinergic receptors. The ion transport properties of these lines differed from the normal lines and approximated those of primary CF airway epithelial cell cultures more closely than do those of cell lines transformed with the simian virus 40 large T gene. When transplanted into denuded tracheal grafts, these cells can differentiate into ciliated and secretory phenotypes. We conclude that HPV-18 E6 and E7 genes are sufficient to transform human airway epithelial cells and that the resultant cell lines express differentiated phenotypic properties that approximate those of the native epithelium.
ER mRNA was detected as 6.0 kb band by Northern blot analysis in vascular smooth muscle cells (VSMC) derived from rat aorta. The presence of ER mRNA in VSMC was confirmed by reverse transcriptase-polymerase chain reaction using specific primers for rat ER cDNA. In addition, the immunocytochemistry of ER was performed in VSMC using a monoclonal anti-ER antibody which recognizes DNA-binding domain of ER. The immunoreactivity was distributed in the cytoplasm as well as in the nuclei. Thus, the expression of ER in VSMC was demonstrated at both the protein and the mRNA level. Furthermore, the expression of c-fos mRNA in VSMC was found up-regulated by 17 beta-estradiol treatment within 30 min. The observation that VSMC possess ER and respond to estrogen supports the idea that estrogen may directly influence vascular cell system through the ER.
Treatment of ovariectomized rats with the nonsteroidal antiestrogen tamoxifen mimicked the effects of estradiol and caused significant decreases in food intake and body weight. The decreases in body weight were reflected mainly in a decreased body fat content, although tamoxifen treatment did suppress linear growth too. Similar to the effects of estradiol, tamoxifen decreased parametrial white adipose tissue wet weight and lipoprotein lipase activity. When given concurrently with estradiol, tamoxifen showed no evidence of antiestrogenic activity on any of these measures. As reported previously, tamoxifen acted as a partial agonist/antagonist for uterine weight. The effective dose of tamoxifen for suppression of food intake, body weight, and body fat content fell between 10 and 50 micrograms/day. Therefore, tamoxifen behaves like other nonsteroidal antiestrogens and mimics but fails to antagonize the actions of estradiol on many aspects of physiological and behavioral regulation of energy balance.
Clinical evidence suggests that sex hormones affect adipose tissue metabolism and deposition. To investigate the biosynthesis and possible action of estrogen in adipose tissue, we report the use of competitive, specific polymerase chain reaction amplifications to determine levels of estrogen receptor (ER) messenger RNA (mRNA) and cytochrome P450 aromatase mRNA in adipocytes and adipose stromal cells. This extremely sensitive technique uses coamplification of a homologous animal species complementary RNA to control for differences in amplification efficiencies. The DNA amplification products are identified by Southern hybridization with species-specific radiolabeled oligonucleotide probes. Abdominal adipose tissue obtained from female patients during elective abdominoplasty was separated by collagenase digestion and centrifugation into floating adipocytes and pelleted adipose stromal cells. Our results demonstrate higher ER mRNA levels in adipocytes compared to adipose stromal cells, whereas cytochrome P450 aromatase mRNA levels are higher in adipose stromal cells compared to adipocytes. The finding of ER mRNA in adipose tissue suggests the presence of the ER in adipose tissue. In addition the inverse correlation of ER mRNA and cytochrome P450 aromatase mRNA levels in adipocytes and adipose stromal cells suggests a paracrine relationship whereby estrogen produced by adipose stromal cells affects adjacent adipocytes.
The regulation of adipose tissue distribution is an important problem in view of the close epidemiological and metabolic associations between centralized fat accumulation and disease. With visceral fat accumulation multiple endocrine perturbations are found, including elevated cortisol and androgens in women, as well as low growth hormone (GH) and, in men, testosterone (T) secretion. These abnormalities probably derive from a hypersensitive hypothalamo-pituitary-adrenal axis, with hyperinsulinemia related to a marked insulin resistance as a consequence. These hormonal changes exert profound effects on adipose tissue metabolism and distribution. At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity, while T, GH and probably estrogens exert opposite effects. The consequences will most likely be more expressed in visceral than subcutaneous adipose tissues because of a higher cellularity, innervation and blood flow. Furthermore, the density of cortisol and androgen receptors seems to be higher in this than other adipose tissue regions. The endocrine perturbations found in visceral obesity with an abundance of the lipid accumulating hormones cortisol and insulin, and a relatively low secretion of the lipid mobilizing sex steroid hormones and GH would therefore be expected to be followed by visceral fat accumulation. The potential significance of local synthesis of steroid hormones in adipose tissue requires more attention. Although studies in vitro are informative when elucidating detailed mechanisms of hormonal interactions, they might not give a true picture of the regional integrated regulation of adipose tissue lipid storage and mobilization. Such information can be obtained by regional measurements of lipid mobilization by free fatty acid turnover or by microdialysis techniques, both showing lower rates of mobilization in leg than in upper body adipose tissues. More detailed information can be obtained by physiological oral administration of triglycerides, labelled with a small amount of oleic acid, followed by measurements of the regional uptake and turn-over of adipose tissue triglycerides. Such studies show lipid uptake in the order omental = retroperitoneal > subcutaneous abdominal > subcutaneous femoral adipose tissues in men, with a similar rank order for half-life of the triglyceride, indicating also a turn-over of triglycerides in that order. T amplifies these differences in men. In premenopausal women subcutaneous abdominal has a higher turnover than femoral adipose tissue. Results of studies in vitro indicate that this difference is diminished at the menopause, and restored by estrogen substitution, suggesting that the functional effects of estrogens in women are similar to those of T in men. The mechanisms are, however, probably indirect because of the apparent absence of specific estrogen and progesterone receptors in human adipose tissue. This interpretation from the studies referred to above fits well with physiological, and clinical conditions with increased visceral fat mass, where the balance between the lipid accumulating hormone couple (cortisol and insulin) and the hormones which prevent lipid accumulation and instead activate lipid mobilization pathways (sex steroid hormones and GH) is shifted to the advantage of the former. Such conditions include Cushing's syndrome, the polycystic ovary syndrome, menopause, aging, GH-deficiency, depression, smoking and excess alcohol intake. With appropriate interventions against hypercortisolemia and substitution of deficient sex steroids and GH, visceral fat mass is decreasing. Based on this evidence from physiological, clinical, interventional observations and detailed studies of mechanisms at cellular and molecular levels it is suggested that the combined endocrine abnormalities in the syndrome of visceral obesity direct storage fat to visceral adipose depots. Therefore, measurements of visceral fat accumulat
Estrogen plays a major role in the delayed expression of coronary heart disease (CHD) in women, and recent data indicate that postmenopausal estrogen therapy reduces the incidence of CHD by > 40%. The mechanism or mechanisms through which estrogen exerts this benefit are unknown, although effects on blood pressure, carbohydrate and lipid metabolism, and coagulation have been suggested. We hypothesized that at least part of the effect of estrogen in reducing the incidence of CHD is due to an effect on endothelial cell function.
In the present study, we examined human aortic and umbilical vein endothelial cells and bovine aortic endothelial cells for the presence of estrogen receptors (ERs) through immunoblot and mRNA analyses. Electrophoretic mobility shift assays were also performed to determine the DNA-binding properties of the putative ERs. Nuclear extracts from all three endothelial cell types were found to contain a 67-kD protein that reacted with anti-ER monoclonal antibodies specific to different domains of the ERs. Each of these types of cells expresses proteins that bind specifically to consensus estrogen-responsive elements. Finally, Northern blots verified that endothelial cells express abundant amount of mRNA for the ER.
These data indicate that endothelial cells constitutively possess the potential for transcriptional regulation of target genes by estrogen. The evolutionary conservation of this receptor in bovine and human endothelial cells suggests a common mechanism for estrogen regulation of endothelial function.
Various clinical and epidemiological evidence strongly suggests a major role for sex steroid hormones in the determination of anatomical specificities of fat distribution in human. To date, no studies have examined the possible presence of androgen receptors (AR) in human adipocytes and preadipocytes. We have studied AR in preadipocytes from various anatomical locations (intra-abdominal and subcutaneous) in middle-aged men and women during the proliferation and differentiation processes (adipogenesis). Androgen binding sites quantified by [3H]R-1881-specific binding in whole cell extracts were twofold higher in intra-abdominal than in subcutaneous preadipocytes but identical for the same fat depots in men and women. Western blot analysis revealed 1) the presence of AR in the nuclear and cytosolic fractions of human preadipocytes, 2) a decrease of AR expression during adipogenesis, and 3) an upregulation of AR by androgens in vitro. RT-PCR experiments showed the presence of AR mRNA in human preadipocytes and adipocytes and also the regional specificity of AR distribution. However, AR mRNA expression was found to increase during adipogenesis. The same results were observed in rat preadipocytes. In conclusion, this study clearly demonstrates the presence of AR in human preadipocytes and adipocytes and suggests that androgens may contribute, through regulation of their own receptors, to the control of adipose tissue development.
Leptin is a hormone secreted by the adipocytes to serve as a signal to the central nervous system to regulate energy homeostasis. Circulating leptin mainly reflects both total fat mass and the size of constituent adipocytes, although other ancillary hormonal factors may contribute to its blood concentration. Relevant gender differences in leptin concentrations have been reported, but it is not clear whether the elevated leptin levels in women are an intrinsic property of their adipocytes or merely reflect a greater amount of fat reserves.
To clarify these points, a systematic study with organ culture from human omental adipose tissue either stimulated or not with steroid hormones was undertaken in samples obtained at surgery from 67 nonobese donors (33 women and 34 men). The assay was standardized in periods of 24 h ending at 96 h, with no apparent tissue damage. Each adipose tissue sample from a single donor was incubated in triplicate, and leptin results are expressed as the mean ± sem of the integrated secretion to the medium (area under the curve; nanograms of leptin per g tissue/48 h).
Control nonstimulated samples showed a steady leptin secretion along the 96 h studied, with the peak of secretory activity reached at 48 h; afterward, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in samples from 33 women (3904 ± 347) was significantly higher (P < 0.05) than that in samples from 34 men (2940 ± 323). Coincubation of adipose tissue with 1 μmol/L dexamethasone induced a clear-cut leptin increase (P < 0.05) in samples from women (5848 ± 624; n = 12), but did not change the spontaneous release of leptin in samples from men (3353 ± 741; n = 6). Similarly, coincubation of adipose tissue with 1 μmol/L estradiol induced a notable leptin increase (P < 0.05) in samples from women (5698 ± 688; n = 9), whereas it did not alter the secretion in the male samples (3373 ± 444; n = 6). In samples from both sexes, coincubation with 1 μmol/L estrone or progesterone had no effect, whereas 1 μmol/L forskolin significantly (P < 0.05) reduced leptin release.
In conclusion, leptin secretion from omental adipose tissue in vitro 1) is significantly higher in samples from women than in samples from men, 2) is stimulated by dexamethasone and estradiol in women but not in men, 3) is not modified by progesterone or estrone in both sexes, and 4) is inhibited by forskolin in both genders. This different response to the stimulation of adipose tissue may be the biological basis for the gender differences observed in circulating levels of human leptin.
The effect of the isoflavone, genistein, on the lipid metabolism of ovariectomized rats was studied. Three types of experiments were performed. In the first one, the rats were fed diets supplemented with 0.01 or 0.1% of genistein for 14 days. In the second and third experiments, the direct effect of genistein on the liver and fat tissue were measured respectively by means of liver perfusion or incubation of isolated adipocytes with the isoflavone. Genistein in food significantly decreased blood serum and muscle triglyceride concentrations and increased the level of free fatty acids in serum. Serum free cholesterol was diminished and liver cholesterol was enhanced after genistein ingestion. When genistein acted directly on the liver during perfusion, a smaller incorporation of 14C-glucose into lipids was observed, and in parallel a greater output of free fatty acids into the medium was noticed. These changes were accompanied by diminution of the liver triglyceride contents. Genistein, acting on the adipocytes strongly depressed both basal and insulin-induced lipid synthesis, when glucose was used as a substrate. The effect of the isoflavone alone on the lipolysis in the adipocytes was negligible. However, it intensified lipolysis induced by epinephrine. The results obtained let us conclude that genistein in food can reduce the fattening processes in ovariectomized rats. This effect of genistein may be attributed, at least in part, to its direct influence on lipid metabolism in the liver and adipose tissue.
The purpose of the present study was to determine if the anti-adipogenic effects of dehydroepiandrosterone (DHEA) are mediated solely by DHEA or by one or more of its downstream metabolites. In Experiment 1, preconfluent proliferating cultures of 3T3-L1 preadipocytes were incubated for either 24 or 72 h with 0, 1, 5 or 25 microM DHEA, DHEA sulfate (DHEAS), testosterone, estrone and 17beta-estradiol. Pregnenolone, a precursor of DHEA(S), was also tested at these concentrations. After 24 h of incubation, DHEAS, 17beta-estradiol and estrone at the 1 microM level stimulated preadipocyte proliferation. In contrast, DHEA and 17beta-estradiol at the 25 microM level attenuated proliferation to a greater extent than all other steroids. After 72 h of incubation, DHEA and 17beta-estradiol at the 25 microM level attenuated proliferation to a greater extent than all other steroids. In Experiment 2, post-confluent cultures of differentiating 3T3-L1 preadipocytes were incubated for 6 days with 0, 5, 30, or 60 microM levels of these steroids. Preadipocyte differentiation, as assessed by lipid content and glycerol-3-phosphate dehydrogenase activity, decreased markedly when treated with 30 and 60 microM DHEA, 17beta-estradiol, estrone and pregnenolone. In contrast, DHEAS had no impact on preadipocyte proliferation or differentiation. These results suggest that the anti-adipogenic actions of DHEA in adipose tissue may be mediated, in part, by one or more of its distal metabolites, including 17beta-estradiol.
Normative body composition during the first 2 y of life was derived from a prospective study of 76 children. We present 1) fat free mass (FFM) and its components, and fat mass (FM), 2) incremental growth rates partitioned into chemical components, and 3) age-specific and gender-specific constants for converting chemical and physical components into FFM for children during the first 2 y of life. A multicomponent model based on measurements of total body water (TBW), total body potassium (TBK) and bone mineral content (BMC) was used to estimate FFM and FM at 0.5, 3, 6, 9, 12, 18, and 24 mo of age. TBW was determined by deuterium dilution, TBK by whole body counting, and BMC by dual energy x-ray absorptiometry. FFM was higher in boys than girls between 0.5-18 mo of age (p < or = 0.05). Percent FM increased on average from 13 to 31% between 0.5 and 3-6 mo, and then gradually declined. Percent FM was significantly higher in girls than in boys at 6 and 9 mo of age (p < or = 0.02). The components of FFM on a percentage basis changed with age (p = 0.001), but not gender. The protein content of FFM increased gradually with age, while TBW declined (p = 0.001). As a percentage of FFM, osseous mineral increased from 2.0 to 3.4% in boys and from 2.1 to 3.3% in girls between 0.5 and 24 mo (p = 0.001). Density and potassium content of FFM increased gradually with age (p = 0.001). These normative body composition data provide an updated reference upon which to assess normal growth and nutritional status of pediatric populations representative of mixed feeding groups during the first 2 y of life.
Estrogen regulates the amount of white adipose tissue (WAT) in females, but its role in males and whether WAT effects involve estrogen receptor-alpha (ERalpha) or ERbeta were unclear. We analyzed the role of ERalpha in WAT and brown adipose tissue by comparing these tissues in wild-type (WT) and ERalpha-knockout (alphaERKO) male and female mice. Brown adipose tissue weight was similar in alphaERKO and WT males at all ages. Progressive increases in WAT were seen in alphaERKO males with advancing age. Epididymal, perirenal, and inguinal WAT weighed 139-185% more in alphaERKO than in WT males by 270-360 days of age. Epididymal and perirenal adipocyte size was increased 20% in alphaERKO males. Adipocyte number was 82-168% greater in fat pads of alphaERKO vs. WT males. Compared with WT, 90-day-old alphaERKO females had increases in fat pad weights (54-103%), adipocyte size, and number. Both alphaERKO males and females had insulin resistance and impaired glucose tolerance, similar to humans lacking ERalpha or aromatase. Energy intake was equal in WT and alphaERKO males, indicating that obesity was not induced by hyperphagia. In contrast, energy expenditure was reduced by 11% in alphaERKO compared with WT males, indicating that altered energy expenditure may be important for the observed obesity. In summary, ERalpha absence causes adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose intolerance in both sexes. These results are evidence that estrogen/ERalpha signaling is critical in female and male WAT; obesity in alphaERKO males involves a mechanism of reduced energy expenditure rather than increased energy intake.