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Dehydroepiandrosterone prevents age-associated alterations, increasing insulin sensitivity
Abstract
The age decline in DHEA levels has been associated with the appearance of age-related disorders such as obesity and insulin resistance. The aim of this study was to analyse the effect of chronic administration (13 weeks) of DHEA (5 g/kg diet) to old female rats fed on a high-fat diet on body weight and adiposity, and concretely on the expression of the adipokines related to obesity and insulin resistance, such as leptin, adiponectin and resistin. DHEA treatment induced a decrease in body weight, adipose tissue mass and serum insulin, adiponectin and leptin levels. Adiponectin mRNA expression in visceral fat depots decreased with aging, but this reduction was attenuated by DHEA treatment. DHEA treatment also stimulated resistin gene expression in the ovaric and renal adipose depots, which is associated with an increase in its circulating levels. In conclusion, DHEA treatment decreases body weight and adiposity in old female rats fed a high-fat diet, leading to an improvement of the HOMA index for insulin sensitivity, with decreasing circulating insulin levels, and preventing the age-associated decline of visceral-adipose adiponectin expression.
... However, the impact of DHEA treatment on glucose metabolism in postmenopausal women remains unclear. Previous reports have shown that DHEA improved adiposity, lipid metabolism, and insulin sensitivity in both humans [15][16][17] and rodents [17][18][19][20][21]. From the cardiovascular point of view, DHEA also has a beneficial effect on reducing oxidative stress in cardiomyocytes [22,23], as well as ameliorates endothelial dysfunction [23][24][25] and systolic and diastolic blood pressure [26,27], decreasing the cardiovascular risk; however, there is some controversy [28][29][30][31][32]. ...
... DHEA not only was able to reduce adiposity in animal models but also had a protective effect against the insulin resistance induced by a high-fat diet [47]. Long-term treatment of old female Sprague-Dawley rats with 0.5% DHEA for 13 weeks [21] or via gavage (50 mg/kg body weight/day/8 weeks) [19] induced lower body weight, over 50% reduction of the fat body mass and leptin blood levels after an obesogenic diet as compared to control rats. Indeed, a decreased adipocyte size in several fat pads after DHEA supplementation in both male and female rats was also reported [21,[48][49][50]. ...
... Long-term treatment of old female Sprague-Dawley rats with 0.5% DHEA for 13 weeks [21] or via gavage (50 mg/kg body weight/day/8 weeks) [19] induced lower body weight, over 50% reduction of the fat body mass and leptin blood levels after an obesogenic diet as compared to control rats. Indeed, a decreased adipocyte size in several fat pads after DHEA supplementation in both male and female rats was also reported [21,[48][49][50]. ...
Dehydroepiandrosterone (DHEA), mostly present as its sulfated ester (DHEA-S), is an anabolic hormone that naturally declines with age. Furthermore, it is the most abundant androgen and estrogen precursor in humans. Low plasma levels of DHEA have been strongly associated with obesity, insulin resistance, dyslipidemia, and high blood pressure, increasing the risk of cardiovascular disease. In this respect, DHEA could be regarded as a promising agent against metabolic syndrome (MetS) in postmenopausal women, since several age-related metabolic diseases are reported during aging. There are plenty of experimental evidences showing beneficial effects after DHEA therapy on carbohydrate and lipid metabolism, as well as cardiovascular health. However, its potential as a therapeutic agent appears to attract controversy, due to the lack of effects on some symptoms related to MetS. In this review, we examine the available literature regarding the impact of DHEA therapy on adiposity, glucose metabolism, and the cardiovascular system in the postmenopausal period. Both clinical studies and in vitro and in vivo experimental models were selected, and where possible, the main cellular mechanisms involved in DHEA therapy were discussed.
Schematic representation showing some of the general effects observed after administration DHEA therapy on target tissues of energy metabolism and the cardiovascular system. ↑ represents an increase, ↓ represents a decrease, – represents a worsening and ↔ represents no change after DHEA therapy
... Exogenously administered DHEA inhibited fat accumulation or reduced visceral fat pads in young and adult rodents [14,15,16,17,30]. DHEA has also been shown to protect against visceral obesity in rats fed a high-fat diet [29,31]. In aging female rats fed a high-fat diet, a 3-month treatment with DHEA (0.5%) led to a decrease in adipocyte size in various white fat depots [31]. ...
... DHEA has also been shown to protect against visceral obesity in rats fed a high-fat diet [29,31]. In aging female rats fed a high-fat diet, a 3-month treatment with DHEA (0.5%) led to a decrease in adipocyte size in various white fat depots [31]. Interestingly, DHEA-treated rats showed a significant decrease in adipocyte diameter in ovarian and mesenteric but not subcutaneous fat pad [31]. ...
... In aging female rats fed a high-fat diet, a 3-month treatment with DHEA (0.5%) led to a decrease in adipocyte size in various white fat depots [31]. Interestingly, DHEA-treated rats showed a significant decrease in adipocyte diameter in ovarian and mesenteric but not subcutaneous fat pad [31]. This finding indicates that visceral adipose tissue is more sensitive to DHEA than subcutaneous fat. ...
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the major circulating adrenal steroids and serve as substrates for sex hormone biosynthesis. DHEA is effectively taken up by adipose tissue, where the concentrations of free DHEA are four to ten times higher than those found in the circulation. DHEA reduces adipose tissue mass and inhibits the proliferation and differentiation of adipocytes; it may also protect against obesity by lowering the activity of stearoyl-CoA desaturase 1 in fat cells. Recent studies demonstrate that DHEA stimulates triacylglycerol hydrolysis in adipose tissue by increasing the expression and activity of adipose triglyceride lipase and hormone-sensitive lipase, the key enzymes of lipolysis. DHEA has been shown to modulate insulin signaling pathways, enhance glucose uptake in adipocytes, and increase insulin sensitivity in patients with DHEA deficiency or abnormal glucose tolerance. Additionally, by suppressing the activity of 11β-hydroxysteroid dehydrogenase 1 in adipocytes, DHEA may promote intra-adipose inactivation of cortisol to cortisone. Several studies have demonstrated that DHEA may also regulate the expression and secretion of adipokines such as leptin, adiponectin, and resistin. The effects of DHEA on adipokine expression in adipose tissue are depot-specific, with visceral fat being the most responsive. The mechanisms underlying DHEA actions in adipose tissue are still unclear; however, they involve nuclear receptors such as androgen receptor and peroxisome proliferator-activated receptors γ and α. Because clinical trials investigating the effects of DHEA failed to yield consistent results, further studies are needed to clarify the role of DHEA in the regulation of human adipose tissue physiology.
... Interestingly, a specific receptor for DHEA still has not been identified. This steroid has anti-inflammatory effects, reduces the risk of cardiovascular diseases as well as fat accumulation, protects against insulin resistance in both humans [12,13] and rodents [11,[14][15][16], and inhibits breast cancer cell line proliferation and migration [17]. ...
... We found that OVX rats displayed an increased feeding efficiency that was reflected in an increased body mass and adiposity index. While previous reports have shown that DHEA supplementation reduced adiposity and improved insulin sensitivity in both humans [12,13] and rodents [11,[14][15][16], we did not observe any reduction in the body weight or adiposity. It was previously demonstrated that ovariectomy, as well as a high-fat diet, induce changes in estrogen receptor alpha (ERα) expression in the adipose tissue, which is the main mediator of estradiol effects on energy homeostasis [43]. ...
Aims:
Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone that is a precursor of sexual hormones. It is reduced during aging and is strongly associated with insulin resistance and obesity. There is evidence for beneficial effects of this steroid, in both human and animal models, during perimenopause. However, the impact of DHEA treatment during late postmenopause on glucose metabolism is not clearly documented. We tested the hypothesis that DHEA supplementation could improve insulin sensitivity in an ovariectomized obese rat model (OVX) that was fed a high-fat diet for 11 weeks.
Main methods:
Female Wistar rats at 8 weeks of age were OVX or SHAM-operated. Eight weeks after the surgery, the animals were randomly treated with vehicle or DHEA for 3 weeks. Food intake, metabolic parameters and insulin sensitivity were evaluated.
Key findings:
Following the ovariectomy, increased body weight gain, adiposity index, and feeding efficiency were observed, despite there being no change in food and energy intake. The OVX rats also displayed glucose intolerance, insulin resistance, decreased insulin-induced IRS1/2 tyrosine phosphorylation in the skeletal muscle, and reduced serum VLDL-c and TAG levels. OVX rats treated with 10 mg/kg DHEA (OVX + DHEA) exhibited estradiol (E2) serum levels similar to SHAM animals, with no change in uterus mass. DHEA treatment also resulted in an increase in energy intake.
Significance:
Despite the positive effects of DHEA supplementation observed in menopausal women and ovariectomized rats, a potential negative effect on glucose metabolism and insulin action in the late postmenopausal condition in diet-induced obese OVX rats are reported.
... Animal experiments indicated beneficial effect of DHEA on metabolism and renal injury despite conflicting results shown by epidemiological studies. In old female rats, DHEA treatment could change fatty acid profiles in serum and adipose tissue, decrease body weight and adiposity, and, thus, increase insulin sensitivity (26,27). For dexamethasone-treated or diabetic rabbits, DHEA improved insulin sensitivity, lipid levels, directly inhibited renal gluconeogenesis, delayed the onset of diabetes, and alleviated renal oxidative stress and albuminuria (28)(29)(30). ...
Background
The associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with diabetic kidney disease (DKD) remained unclear. Thus, this cross-sectional study aimed to explore the associations of DHEA and DHEAS with the risk of DKD in patients with T2DM.
Methods
The information of 1251 patients with T2DM were included in this study. Serum DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry assays. Multivariate logistic regression analyses were used to assess the associations of DHEA and DHEAS with DKD as well as high urine albumin to creatinine ratio (ACR).
Results
In men with T2DM, the risk of DKD decreased with an increasing DHEA concentration after adjustment for traditional risk factors; the fully adjusted OR (95% CI) for tertile3 vs tertile1 was 0.37 (0.19-0.70; P = 0.010 for trend). Similarly, when taking high ACR as the outcome, low DHEA levels were still significantly associated with increased odds of high ACR (OR, 0.37; 95% CI, 0.19–0.72 for tertile3 vs tertile1; P = 0.012 for trend). The restricted cubic spline showed that the risk of DKD gradually decreased with the increment of serum DHEA levels (P-overall = 0.007; P-nonlinear = 0.161). DHEAS was not independently associated with the risk of DKD in men. In contrast, no significant relationships were found between DHEA and DHEAS and the risk of DKD in women (all P > 0.05).
Conclusions
In men with T2DM, low serum DHEA levels were independently related to the risk of DKD after adjustment for traditional risk factors. Our finding highlights the potential role of DHEA in the development of DKD in men with T2DM.
... The relationship between total SFA and DHEA-S was mainly attributed to a concomitant increase of palmitic acid (16:0). The negative correlation between palmitic acid and DHEA-S may explain some of the beneficial properties of DHEA-S which may contribute to improve insulin sensitivity [20]. Palmitic acid seems to impair insulin sensitivity by its conversion into ceramides, which interference with the insulin signaling pathway [21]. ...
The aim of this study is to investigate the association between endogenous dehydroepiandrosterone sulfate (DHEA-S) and fatty acid, desaturase in isolated post-challenge hyperglycemia (IPH) subjects. 241 IPH subjects aged 35 to 70 years participated. Serum DHEA-S concentration was measured using the enzyme-linked immunosorbent assays. Fatty acid profiles were detected by gas chromatography-mass spectrometry, and desaturase activities were expressed by fatty acid product-to-precursor ratios. Relationships were assessed using multiple regression. The results suggested that DHEA-S concentration was negatively associated with palmitic acid (P < 0.001), and positively with γ-linolenic acid and eicosatetraenoic acid in men (P = 0.002 and P = 0.001, respectively), and negatively with palmitic acid (P = 0.037) and positively with docosapentaenoic acid, docosahexaenoic acid (P = 0.018 and P < 0.001, respectively) in women. In addition, a positive association was observed between DHEA-S and delta-9-desaturase (D9D-18, P = 0.031) in men, and also delta-6-desaturase (D6D, P = 0.034) in women. In Conclusions, there is different DHEA-S, fatty acid profile and the desaturase activities in both genders with the IPH subjects.
... Body weight gain and visceral fat accumulation can be reduced by dehydroepiandrosterone (DHEA) administration [12]. DHEA, a hormone synthesized by the adrenal cortex [13], is an attractive therapeutic alternative for perimenopausal women owing to its widely known beneficial effects, such as reduction of cardiovascular risk and increase of insulin sensitivity [14]. Studies on humans demonstrate an inverse relationship between serum DHEA levels and obesity [15]. ...
Several studies have investigated the beneficial effects of dehydroepiandrosterone (DHEA) on lipid and glucose metabolism. However, many of these studies are inconclusive about the effects of DHEA administration on metabolic disorders, and there appear to be sex-related differences in the effects of DHEA treatment. Few animal studies have addressed the effects of DHEA on diet-induced metabolic disorders. The present study sought to ascertain whether sex differences exist in the effects of a high-fat diet (HFD) on weight gain, adiposity, and biochemical and hormonal parameters in DHEA-treated rats. Rats were fed a HFD for 4 weeks and simultaneously received treatment with DHEA (10 mg/kg by subcutaneous injection) once weekly. Body weight, retroperitoneal fat depot weight, serum glucose, insulin, and leptin levels, and hepatic lipids were measured. HFD exposure increased the adiposity index in both sexes, the hepatic triglyceride content in both sexes, and the hepatic total cholesterol level in males. Moreover, the HFD induced an increase in blood glucose levels in both sexes, and hyperinsulinemia in males. In this experimental model, DHEA treatment reduced hepatic triglyceride levels only in females, regardless of HFD exposure. Exposure to a HFD, even if it does not cause obesity, may enhance risk factors for metabolic disorders, and males are more sensitive to this effect. DHEA treatment can help prevent metabolic derangements, but its effect varies with sex.
... The DHEA concentration in the serum and age are negatively correlated. This relationship suggests two possibilities, namely, that the production of DHEA decreases with age and that the expression of DHEA increases in the adipose tissue [31]. However, the exact mechanisms are still unknown. ...
Adipose stem cells (ASCs) are pluripotent cells that can generate pure fat tissue for regeneration. Differentiated adipose cells have been generated by a common inducer cocktail composed of dexamethasone, insulin, and isobutylmethylxanthine (DIM). The major drawbacks of adipose cells are their tendency to float on the culture media and their cost. To overcome some of these disadvantages, a new inducer cocktail that includes insulin, dehydroepiandrosterone, and histamine (DH IH) was tested. As a result, lipid accumulation was elevated more than twofold with DH IH than with DIM. Cell adhesion and viability, which are important factors for stable differentiation, were increased with DH IH and were proven through measurement of mRNA expression levels of adhesion marker genes, N-cadherin and vascular cell adhesion molecule, as well as through an alamar blue assay. The expression of adipogenesis-related genes, adiponectin, and glucose transporter type 4 lasted for a long time. To improve the efficiency of grafting, cell adhesion and neovascularization need to be increased. Neovascularization was observed around the transplanted adipose cells, which showed a higher number of vessel formation in DH IH than in DIM. The above results suggest that DH IH can produce pure differentiated adipose cells effectively and enhance their adhesion onto the target location when these differentiated adipose cells were applied as a clinical resource.
... Moreover, brief exercise significantly increases muscular levels of DHEA and steroidogenesis-related enzymes[5,6]. Exercise training is beneficial for patients with insulin resistance and hyperinsulinemia[26,27]. Although exercise training has been shown to improve insulin resistance and glucose metabolism in obese patients with type 2 diabetes, most effects are observed after longer exercise programs.Therefore, combination treatment may be more beneficial than either therapy alone. ...
Dehydroepiandrosterone (DHEA) is precursor of sex steroid hormone. We demonstrated that acute DHEA injection to type 1 diabetes model rats induced improvement of hyperglycemia. However, the effect of the combination of DHEA administration and exercise training on insulin resistance is still unclear. This study was undertaken to determine whether 6-weeks of DHEA administration and/or exercise training improve insulin resistance in obese male rats.
After 14 weeks of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of four groups: control, DHEA administration, exercise training, and a combination of DHEA administration and exercise training (n = 10 each group).
After 6-weeks of DHEA administration and/or exercise training, rats in the combination group weighed significantly less and had lower serum insulin levels than rats in the other groups. Moreover, the rats treated with DHEA alone or DHEA and exercise had significantly lower fasting glucose levels (combination, 84 ± 6.5 mg/dL; DHEA, 102 ± 9.5 mg/dL; control, 148 ± 10.5 mg/dL). In addition, insulin sensitivity check index showed significant improvements in the combination group (combination, 0.347 ± 0.11; exercise, 0.337 ± 0.16%; DHEA, 0.331 ± 0.14; control, 0.308 ± 0.12). Muscular DHEA and 5α-dihydrotestosterone (DHT) concentrations were significantly higher in the combination group, and closely correlated with the quantitative insulin-sensitivity check index (DHEA: r = 0.71, p < 0.01; DHT: r = 0.69, p < 0.01).
These results showed that a combination of DHEA administration and exercise training effectively improved fasting blood glucose and insulin levels, and insulin sensitivity, which may reflect increased muscular DHEA and DHT concentrations.
... It is important to note that the positive association between adipose tissue and DHEA/S production outlined in this section appears to contradict the usual picture of DHEA/S administration as having anti-obesity and anti-diabetic properties in rodents (Cleary 1991;Sánchez et al. 2008) and, more important, human adults (Villareal and Holloszy 2004, but see Basu et al. 2007). However, the majority of findings on DHEAS in humans are based on adults, who are much more likely than children to exhibit central obesity, which has been linked to endogenous DHEAS titers (Derby et al. 2006). ...
... 12,13 Our group has taken a deeper look at the metabolic effect of this hormone in experimental models and in in vitro adipose tissue cultures and found that the hormone is able to stimulate adipose tissue lipolysis, reduce fat accumulation and decrease energy intake. 14,15 In addition, plasma levels of several peptides, such as leptin, adiponectin and ghrelin, which could play an important role in the genesis of MetS and cardiovascular diseases, [16][17][18] were also seen to be related with DHEA-S levels in experimental models. 18,19 However, and in spite of this knowledge, no studies in humans have focused on a comprehensive evaluation of the effect of a replacement therapy with this hormone and the parameters that define MetS as a whole. ...
Objective To analyze the effect in obese pre- and postmenopausal women of a daily dose of 100 mg dehydroepiandrosterone-sulphate (DHEA-S) provided over a period of 3 months as replacement therapy against metabolic syndrome.
Context Although DHEA-S appears to be effective against certain features of metabolic syndrome, its usefulness against this syndrome as a whole has not been evaluated to date.
Design/Patients A randomized, double-blind placebo-controlled trial was conducted involving 61 postmenopausal women, who received DHEA-S (n = 41) or placebo (n = 20) for 3 months. The effect of DHEA-S treatment on the same postmenopausal women was compared with the effects observed in a group of premenopausal women (n = 20).
Measurements Anthropometric measurements were taken at the beginning and at the end of the treatment. Similarly, different parameters that define metabolic syndrome and other cardiometabolic variables were determined.
Results Dehydroepiandrosterone-sulphate replacement produced weight loss in the obese women studied. Moreover, waist circumference, glucose and systolic and diastolic blood pressure, among other metabolic syndrome parameters, improved in the postmenopausal group, who showed a significant reduction in the total metabolic syndrome score (P < 0·05). In contrast, in premenopausal women, the effect of DHEA-S was limited to obesity parameters, and no effect was observed on metabolic syndrome components. No significant changes were evident in the placebo group.
Conclusions An oral dose of DHEA-S is useful for weight loss. In obese postmenopausal women, the hormone significantly improves plasma biochemical levels and anthropometric characteristics, leading to a better metabolic profile, which highlights the usefulness of this therapy against metabolic syndrome in this group of women.
... The decrease of SFA observed in the present study in both postmenopausal and premenopausal women was associated with a concomitant decrease in myristic acid (14:0), as a consequence of DHEA-S treatment, whereas no effect was observed in the placebo, as expected. The effect of DHEA-S as a SFA-lowering agent is of particular interest as this may explain some of the beneficial properties attributed to this hormone, which may contribute to a decreased cardiovascular disease risk [25] and an improved insulin sensitivity [26]. Currently, nutritional recommendations are directed towards a reduction in saturated fat and an increase in unsaturated fats [15]; in fact, several cross-sectional data suggest that saturated fat adversely affects vascular function whereas unsaturated fat (mainly oleic (18:1n À 9), linoleic acid (18:2n À 6) and n À 3 PUFA) are beneficial [16]. ...
DHEA-S treatment is used as an anti-aging and anti-obesity hormone therapy in adults; however, it mechanisms of action are not clearly elucidated. The objective of the present work was to analyze the effect of a replacement therapy, which included a daily single oral dose of DHEA-S for three months, on the composition of human plasma fatty acids (FAs) in obese women. In the first study, a randomized, double-blind, placebo-controlled trial was conducted involving 61 postmenopausal women, who were assigned to receive 100mg/day of DHEA-S (n = 41) or placebo (n = 20) orally for 3 months. In a second study, the effect of DHEA-S treatment on postmenopausal obese women (n = 41) was compared to that in premenopausal obese women (n = 20). Blood samples were collected at the beginning and at the end of the treatment. Plasma FAs were analyzed by gas chromatography. DHEA-S treatment produced significant changes in plasma FAs of both post- and premenopausal women with a reduction of total saturated FAs (SFA) as well as an increase in n-6 polyunsaturated FA (PUFA). Particularly, in premenopausal women the DHEA-S treatment also increased the plasma n-3 PUFA percentage. Regarding estimation of desaturase activity, our data showed that Δ6-desaturase was significantly decreased in postmenopausal women after DHEA-S treatment, whereas Δ5-desaturase was increased in the premenopausal group. In conclusion, DHEA-S treatment in obese women modifies plasma FA composition towards a potentially better metabolic profile, mainly by decreasing SFA and increasing n-6 PUFA in both postmenopausal and premenopausal women.
... USA) (Arnold 2009). DHEA appears to exert several beneficial effects similar to CR, including anti-cancer, antiobesity, decrease of blood glucose and body temperature, and increase of insulin sensitivity (Yang et al. 2000;Sánchez et al. 2008). It has also been showed that DHEA can inhibit growth and induce apoptosis of murine BV-2 cells and that these effects of DHEA are inversely proportional to the glucose concentration in the medium (Yang et al. 2000(Yang et al. , 2002. ...
2-Deoxy-D-glucose (2-DG) and dehydroepiandrosterone (DHEA) have been hypothesized to extend lifespan via mimicking calorie restriction (CR). Activation of sirtuins has been proposed to contribute to life extension of CR by increasing intercellular levels of NAD(+) in several organisms. However, it is unclear whether 2-DG and DHEA may affect intracellular NAD(+) levels and human sirtuin 1 (SIRT1) activities. Here, using human fibroblast Hs68 cells we showed that 2-DG increased intracellular NAD(+) levels in both time- and concentration-dependent manners. 2-DG also dose-dependently increased SIRT1 activities and the lifespan (measured as the cumulated growth curve of population doubling levels) of Hs68 cells. In contrast, DHEA at non-cytotoxic concentrations (≤50 μM) did not significantly affect NAD(+) levels, SIRT1 activities or the lifespan of Hs68 cells. These results suggest that 2-DG extends the lifespan of Hs68 cells by increased NAD(+) levels and SIRT1 activities, and that 2-DG has a potential as a CR mimetic.
... Patients with metabolic syndrome generally show lower DHEA and DHEA-S levels (4,(22)(23)(24), which mirrors the reduced muscle DHEA and DHT concentrations and 5␣-reductase protein expression that we observed in obese rats. Decreased DHEA levels in obesity and type 2 diabetes may result from insulin-induced inhibition of adrenal 17,20-lyase activity, a key enzymatic step in adrenal androgen synthesis (14). ...
This study was undertaken to assess the effects of dehydroepiandrosterone (DHEA) administration and exercise training on muscular DHEA and 5α-dihydrotestosterone (DHT) levels and hyperglycemia in diet-induced obese and hyperglycemic rats. After 14 wk of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of three 6-wk regimens: control, DHEA treatment, or exercise training (running at 25 m/min for 1 h, 5 days/wk; n = 10 each group). Results indicate that either 6 wk of DHEA treatment or exercise training significantly attenuated serum insulin and fasting glucose levels compared with the control group. Plasma and muscle concentrations of DHEA and DHT and expression levels of 5α-reductase were significantly higher in the DHEA-treated and exercise-training groups. Moreover, both DHEA administration and exercise training upregulated GLUT4 translocation with concomitant increases in protein kinase B and protein kinase Cζ/λ phosphorylation. Muscle DHEA and DHT concentrations closely correlated with blood glucose levels (DHEA treatment: r = -0.68, P < 0.001; exercise training: r = -0.65, P < 0.001), serum insulin levels, and activation of the GLUT4-regulated signaling pathway. Thus, increased levels of muscle sex steroids may contribute to improved fasting glucose levels via upregulation of GLUT4-regulated signaling in diet-induced obesity and hyperglycemia.
... In animal studies (rats), it has been reported that exogenous DHEA administration may lead to a significant reduction in food intake, body weight, total body fat content, the weight of different adipose depots and adipocyte size (de Heredia et al., 2007). In addition, DHEA-treated rats have a significantly lower serum insulin concentration and tended to have a lower HOMA-IR (Sanchez et al., 2008). However, in human studies, exogenous DHEA treatment did not change body composition, insulin sensitivity and metabolic profiles, except decreased HDL-C, in either men or women of advanced age (Morales et al., 1994) or reproductive-aged women with adrenal insufficiency (Allolio and Arlt, 2002;Christiansen et al., 2005). ...
Women with polycystic ovary syndrome (PCOS) are known to have high prevalence of acne and elevated androgen levels. The current study aims to determine if dehydroepiandrosterone sulfate (DHEAS) level is associated with the presence of acne and reduced risk of abdominal obesity in women with PCOS, after considering the concurrent high testosterone level and insulin resistance (IR).
Three hundred and eighteen untreated consecutive Taiwanese women with PCOS were enrolled. Phenotypic hyperandrogenism was recorded, and BMI, waist circumference, waist-to-hip ratio, lipid profiles, fasting glucose and insulin levels and hormone profiles were measured.
Women with acne were younger, had higher serum DHEAS levels (6.01 ± 3.45 versus 4.87 ± 2.49 μmol/l, P = 0.002) and a lower BMI (P = 0.0006), but comparable serum testosterone levels, in comparison with women without acne. The aggravating effect of elevated DHEAS on the risk of acne (odds ratio = 2.15, 95% confidence interval: 1.25-3.68, P = 0.005 for DHEAS cut-off of 6.68 μmol/l) still exited after adjustment for age and BMI. The DHEAS level was positively correlated with the testosterone level, but inversely related to waist circumference, waist-to-hip ratio, BMI, IR index, low-density lipoprotein-cholesterol and triglycerides. Women with PCOS in the highest quartile of DHEAS had the lowest risk of abdominal obesity after adjustment for age, IR, dyslipidemia, testosterone and estradiol levels.
Our results demonstrated the high serum DHEAS in women with PCOS was associated with the presence of acne and a significantly reduced risk of abdominal obesity, independent of serum testosterone concentration and IR.
We previously demonstrated that the addition of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. Using the same study sample, we also sought to determine whether reboxetine's weight-attenuating effect was accompanied by a beneficial effect on metabolic and endocrine parameters relevant to antipsychotic-induced weight gain and obesity.
Blood samples at baseline and at the end of the 6-week trial were available for 54 participants who participated in previous double-blind, placebo-controlled studies of reboxetine (4 mg BID) addition to olanzapine-treated schizophrenia patients. Fasting glucose, lipid profile, insulin, leptin, cortisol, dehydroepiandrosterone (DHEA), prolactin, and thyroid-stimulating hormone (TSH) were analyzed.
In contrast to the olanzapine/placebo group, the olanzapine/reboxetine group exhibited a reduction in blood triglyceride (p < 0.05) and leptin (p < 0.05) levels, and elevation in cortisol (p < 0.05) and DHEA (p < 0.008) levels. No significant between-group differences were detected in the changes in cholesterol, glucose, insulin, TSH, and prolactin.
Reboxetine addition resulted in meaningful improvement of some metabolic and endocrine measures associated with olanzapine-induced weight gain. The potential role of reboxetine in the prevention of olanzapine-induced weight gain and cardio-metabolic morbidity merits further large-scale, long-term investigation.
Background
Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.
Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects.
Results
We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
Conclusions
With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks.
Background
Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.
Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects.
Results
We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
Conclusions
With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks.
To study the association of adrenal and ovarian androgen levels with metabolic parameters in a large cohort of women with polycystic ovary syndrome (PCOS).
Cross-sectional study.
Outpatient clinic of an academic hospital.
Six hundred twenty-two women with PCOS.
None.
Analysis of the association of endocrine dehydroepiandrosterone sulfate (DHEAS) and free testosterone (FT) parameters with metabolic measurements.
In multivariate adjusted logistic regression analyses, the odds ratio (OR) for insulin resistance was statistically significantly higher (4.42, range: 2.26-8.67) for women with PCOS who had elevated FT levels compared with the women with normal DHEAS and FT levels (reference group). We found no statistically significant differences when women with PCOS with elevated DHEAS or a combined elevation of DHEAS and FT levels were compared with the reference group. Women with PCOS and a high DHEAS/FT ratio had a more beneficial metabolic profile compared with the women with a low DHEAS/FT ratio. In multivariate adjusted binary logistic regression analyses, we found a statistically significantly lower risk for insulin resistance in the women with PCOS in the highest DHEAS/FT-ratio quartile compared with women with PCOS in the lowest quartile (OR 0.35, range: 0.14-0.89).
Our results suggest that the distinction between adrenal and ovarian hyperandrogenism is important when evaluating metabolic risk in PCOS.
Middle childhood, the period from 6 to 12 years of age, is defined socially by increasing autonomy and emotional regulation, somatically by the development of anatomical structures for subsistence, and endocrinologically by adrenarche, the adrenal production of dehydroepiandrosterone (DHEA). Here I suggest that DHEA plays a key role in the coordinated development of the brain and body beginning with middle childhood, via energetic allocation. I argue that with adrenarche, increasing levels of circulating DHEA act to down-regulate the release of glucose into circulation and hence limit the supply of glucose which is needed by the brain for synaptogenesis. Furthermore, I suggest the antioxidant properties of DHEA may be important in maintaining synaptic plasticity throughout middle childhood within slow-developing areas of the cortex, including the insula, thamalus, and anterior cingulate cortex. In addition, DHEA may play a role in the development of body odor as a reliable social signal of behavioral changes associated with middle childhood.
Androst-5-ene-3β,7β,17β-triol (βAET) is an anti-inflammatory metabolite of DHEA that is found naturally in humans, but in rodents only after exogenous DHEA administration. Unlike DHEA, C-7-oxidized DHEA metabolites cannot be metabolized into potent androgens or estrogens, and are not peroxisome proliferators in rodents. The objective of our current studies was to characterize the pharmacology of βAET to enable clinical trials in humans. The pharmacology of βAET was characterized by pharmacokinetics, drug metabolism, nuclear hormone receptor interactions, androgenicity, estrogenicity, and systemic toxicity studies. βAET's acute anti-inflammatory activity and immune modulating characteristics were measured in vitro in RAW264.7 cells and in vivo in murine models with parenteral administration. βAET was rapidly metabolized and cleared from circulation in mice and monkeys. βAET was weakly androgenic and estrogenic in immature rodents, but not bound by androgen, estrogen, progesterone, or glucocorticoid nuclear hormone receptors. βAET did not induce peroxisome proliferation, nor was it systemically toxic or trophic for sex hormone responsive tissues in mature rats and monkeys. βAET significantly attenuated acute inflammation both in vitro and in vivo, augmented immune responses in adult mice, and reversed immune senescence in aged mice. βAET may contribute to the anti-inflammatory activity in rodents attributed to DHEA. Unlike DHEA, βAET's anti-inflammatory activity cannot be ascribed to activation of PPARs, androgen, or estrogen nuclear hormone receptors. Exogenous βAET is unlikely to produce untoward toxicity or hormonal perturbations in humans.
This study concentrated on the initial events triggering the development of nonalcoholic fatty liver disease induced by a high-fat plus fructose (HF-F) diet and on the possibility of delaying nonalcoholic fatty liver disease progression by adding dehydroepiandrosterone (DHEA) to the diet. Sterol regulatory element binding protein-1c (SREBP-1c) activation plays a crucial role in the progression of nonalcoholic fatty liver disease induced by an HF-F diet. This study investigated the protective effects of DHEA, a compound of physiological origin with multitargeted antioxidant properties, against the induction of SREBP-1c and on liver insulin resistance in rats fed an HF-F diet, which mimics a typical unhealthy Western diet. An HF-F diet, fortified or not with DHEA (0.01%, w/w), was administered for 15 weeks to male Wistar rats. After HF-F the liver showed unbalanced oxidative status, fatty infiltration, hepatic insulin resistance, and inflammation. The addition of DHEA to the diet reduced both activation of oxidative-stress-dependent pathways and expression of SREBP-1c and partially restored the expression of liver X-activated receptor-alpha and insulin receptor substrate-2 genes. DHEA supplementation of the HF-F diet reduced de novo lipogenesis and delayed progression of nonalcoholic fatty liver disease, demonstrating a relationship between oxidative stress and nonalcoholic fatty liver disease via SREBP-1c.
Dehydroepiandrosterone (DHEA) is reported to exert beneficial effects, such as protection from cardiovascular risk and lowering serum insulin levels. Adipose tissue (AT) is a target for DHEA actions, and the hormone can also affect hepatic fatty acid (FA) metabolism. FAs are involved in the development of insulin resistance; thus, there might be a relationship between DHEA, FA, and insulin. However, few data are available regarding DHEA and FA composition, especially concerning AT. Seventeen-month old female Sprague-Dawley rats (n=11; controls: n=10) were treated with DHEA (0.5% w/w in the diet) for 13 weeks, after which serum, periovarian, mesenteric, s.c., and brown AT were analyzed for FA composition. DHEA treatment resulted in significant changes in FA profiles in serum and adipose depots, like reduced 16:1n-7 (s.c. and brown AT; P<0.01), elevated n-9 monounsaturated FA (serum and s.c. AT; P<0.05), diminished n-6 polyunsaturated FA (PUFA; general; P<0.05) and increased n-3 PUFA (brown AT; P<0.01), along with lower n-6/n-3 ratios (s.c. and brown AT; P<0.05, P<0.01 respectively). DHEA modified estimates of desaturase activities, decreasing stearoyl-CoA-desaturase markers in s.c., and brown AT (P<0.05) and increasing those of delta-6-desaturase in serum and AT (P<0.05). In addition, DHEA-treated rats showed lower serum insulin levels (P<0.05). We have demonstrated for the first time that DHEA induces significant modifications in AT fatty acid composition in vivo, mainly concerning unsaturated FAs, and changes occurred in a tissue-dependent manner. We propose that these changes may be related to the capacity of DHEA to lower serum insulin levels.
Dehydroepiandrosterone (DHEA) has an anti-obesity effect in rodents and reduces body fat in normal men. Therefore, the plasma levels of DHEA were evaluated in nine premenopausal healthy women and in 13 menstrually active nondiabetic obese women, including patients (n = 6) with body mass index (BMI) over 40. In the obese group, a significant inverse correlation between DHEA levels and BMI was found. These results suggest that patients with severe obesity are unable to increase the DHEA adrenal production rate in order to parallel the increase in the hormone metabolic clearance rate (due to enlargement of body fat mass per se). The deficiency of this mechanism might itself contribute to the progressive fat accumulation in severe obesity.
Previous studies showed that administration of dehydroepiandrosterone (DHEA) to lean and genetically obese Zucker rats reduced body weight. In the present experiments, the effect of DHEA treatment in rats with diet-induced obesity was evaluated. In experiment 1, male Sprague-Dawley rats (300 g) were fed a nonpurified diet (reference group) or a condensed milk-corn oil nonpurified diet [diet-induced obese (DIO) rats] for 7 wk. Then, 0.6% DHEA was included in the food of one-half of the DIO rats (DIO + DHEA rats). After 6 wk, DIO rats weighed 23% more and had greater fat pad weights, cell size and cell number than reference and DIO + DHEA rats. Brown fat mitochondrial respiration was similar in all groups. DIO rats had higher serum cholesterol and triacylglycerol concentrations than reference and DIO + DHEA rats. DIO + DHEA rats had lower serum insulin levels than DIO and reference rats. In experiment 2, male Sprague-Dawley rats (460 g) were fed either the nonpurified diet or the condensed milk diet for 8 wk. Condensed milk-fed rats were then divided into DIO and diet-resistant groups. One-half of the rats in each group were fed 0.6% DHEA for 2 wk. Body weights and serum glucose, insulin, triacylglycerol and triiodothyronine levels were lowered by DHEA treatment in all groups. Liver mitochondrial state 3 respiration rates per gram and per liver and peroxisomal beta-oxidation were higher in DHEA-treated than in control rats. In DIO rats, DHEA treatment appears to interfere with hyperplastic adipose tissue growth. In this strain of rats, DHEA appears to have hypolipidemic and hypoinsulinemic effects.
Aging-associated alterations in body composition are accompanied by changes in the endocrine system. We evaluated, in male Brown Norway rats, the effects of aging on body composition and the association with serum levels of leptin, insulin, and testosterone. Body composition was assessed cross-sectionally in male rats (3, 8, 17, and 29 months) by a combination of dual energy x-ray absorptiometry (DEXA) and dissection of specific muscles and adipose depots. Longitudinal changes in body composition were quantified by DEXA before and after 3 months of ad-libitum feeding. Body weight, lean mass, absolute and percentage fat increased with age, whereas percentage of lean mass decreased. Leptin and insulin levels increased with age in proportion to adiposity; the increase in leptin with age was related to increased total and peripheral, but not visceral, fat. Testosterone decreased with age, and was associated with decreased lean and skeletal muscle mass. These findings suggest that alterations in body composition with age may be due to decreased trophic and increased lipogenic hormones. Relative to other rodent models, Brown Norway rats undergo shifts in body composition and in the hormonal milieu that are consistent with changes seen in aging humans.
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).
Obesity has been associated with alterations in plasma steroid hormone concentrations in men. Older men present an altered steroid hormone profile compared to younger individuals, and an increase in body fatness and changes in adipose tissue (AT) distribution are noted with advancing age. Thus, there is a need to examine the relative importance of increased body fatness and changes in AT distribution with advancing age to plasma steroid hormone and sex hormone-binding globulin levels in men. We, therefore, investigated the relationships among age, body fatness, AT distribution, and the plasma steroid hormone profile in a group of 217 Caucasian men (mean age +/- SD, 36.2 +/- 14.9 yr) who covered a wide age range (17-64 yr). Compared to young adult men, older men were characterized by increased adiposity (P < 0.0001) expressed either as body mass index or total body fat mass assessed by underwater weighing. Differences in AT distribution were also noted with a preferential accumulation of abdominal fat as indicated by a larger waist girth (P < 0.0001) and higher visceral AT accumulation (P < 0.0001), measured by computed tomography, in older subjects. Age was associated with decreases (P < 0.0001) in C19 adrenal steroid levels, namely reduced dehydroepiandrosterone (DHEA), DHEA fatty acid ester, DHEA sulfate, as well as androstenedione levels. Androgens, i.e. dihydrotestosterone and testosterone, were also affected by age, with lower levels of both steroids being found in older individuals (P < 0.0005). When statistical adjustment for body fatness and AT distribution was performed, differences in C19 adrenal steroids between the age groups remained significant, whereas differences in androgens and sex hormone-binding globulin concentrations were no longer significant. The present study suggests that age-related differences in plasma steroid hormone levels, especially androgens, are partly mediated by concomitant variation in adiposity in men.
Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.
A 12.5-kDa cysteine-rich adipose tissue-specific secretory factor (ADSF/resistin) is a novel secreted protein rich in serine and cysteine residues with a unique cysteine repeat motif of CX(12)CX(8)CXCX(3)CX(10)CXCXCX(9)CC. A single 0.8-kilobase mRNA coding for this protein was found in various murine white adipose tissues including inguinal and epididymal fats and also in brown adipose tissue but not in any other tissues examined. Two species of mRNAs with sizes of 1.4 and 0.8 kilobases were found in rat adipose tissue. Sequence analysis indicates that this is because of two polyadenylation signals, the proximal one with the sequence AATACA with a single base mismatch from murine AATAAA and the distal consensus sequence AATAAA. The mRNA level was markedly increased during 3T3-L1 and primary preadipocyte differentiation into adipocytes. Its expression in adipose tissue is under tight nutritional and hormonal regulation; the mRNA level was very low during fasting and increased 25-fold when fasted mice were refed a high carbohydrate diet. It was also very low in adipose tissue of streptozotocin-diabetes and increased 23-fold upon insulin administration. Upon treatment with the conditioned medium from COS cells transfected with the expression vector, conversion of 3T3-L1 cells to adipocytes was inhibited by 80%. The regulated expression pattern suggesting this factor as an adipose sensor for the nutritional state of the animals and the inhibitory effect on adipocyte differentiation implicate its function as a feedback regulator of adipogenesis.
Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.
Adiponectin, an adipose tissue-specific plasma protein, was recently revealed to have anti-inflammatory effects on the cellular components of vascular wall. Its plasma levels were significantly lower in men than in women and lower in human subjects with obesity, type 2 diabetes mellitus, or coronary artery disease. Therefore, it may provide a biological link between obesity and obesity-related disorders such as atherosclerosis, against which it may confer protection. In this study, we observed the changes of plasma adiponectin levels with body weight reduction among 22 obese patients who received gastric partition surgery. A 46% increase of mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index. The change in plasma adiponectin levels was significantly correlated with the changes in body mass index (r = -0.5, P = 0.01), waist (r = -0.4, P = 0.04) and hip (r = -0.6, P = 0.0007) circumferences, and steady state plasma glucose levels (r = -0.5, P = 0.04). In multivariate linear regression models, the increase in adiponectin as a dependent variable was significantly related to the decrease in hip circumference (beta = -0.16, P = 0.028), after adjusting body mass index and waist circumference. The change in steady state plasma glucose levels as a dependent variable was related to the increase of adiponectin with a marginal significance (beta = -0.92, P = 0.053), after adjusting body mass index and waist and hip circumferences. In conclusion, body weight reduction increased the plasma levels of a protective adipocytokine, adiponectin. In addition, the increase in plasma adiponectin despite the reduction of the only tissue of its own synthesis suggests that the expression of adiponectin is under feedback inhibition in obesity.
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...
Adipose differentiation is accompanied by changes in cellular morphology, a dramatic accumulation of intracellular lipid and
activation of a specific program of gene expression. Using an mRNA differential display technique, we have isolated a novel
adipose cDNA, termed adipoQ. The adipoQ cDNA encodes a polypeptide of 247 amino acids with a secretory signal sequence at
the amino terminus, a collagenous region (Gly-X-Y repeats), and a globular domain. The globular domain of adipoQ shares significant
homology with subunits of complement factor C1q, collagen α1(X), and the brain-specific factor cerebellin. The expression
of adipoQ is highly specific to adipose tissue in both mouse and rat. Expression of adipoQ is observed exclusively in mature
fat cells as the stromal-vascular fraction of fat tissue does not contain adipoQ mRNA. In cultured 3T3-F442A and 3T3-L1 preadipocytes,
hormone-induced differentiation dramatically increases the level of expression for adipoQ. Furthermore, the expression of
adipoQ mRNA is significantly reduced in the adipose tissues from obese mice and humans. Whereas the biological function of
this polypeptide is presently unknown, the tissue-specific expression of a putative secreted protein suggests that this factor
may function as a novel signaling molecule for adipose tissue.
Resistin is a hormonal factor synthesised by adipocytes that was first thought to be related with the resistance to insulin in obesity, but whose function is not yet completely established. Here we have studied the ontogenic pattern of resistin mRNA expression in different white adipose tissue depots (WAT)--epididymal, inguinal, mesenteric and retroperitoneal--and in brown adipose tissue (BAT), as well as the circulating resistin levels, in rats of different ages (from the suckling period to one year of age). Resistin mRNA was determined by Northern blotting, and serum levels by enzyme immunoassay. In WAT, resistin expression remains almost constant with age, except in early development, where there is a peak of expression in the epididymal and retroperitoneal depots, and a decrease in the inguinal one, while the expression remains constant for the mesenteric depot. Moreover, there is a site-specific difference regarding resistin expression: all the depots express characteristic levels of mRNA, especially at the age of 2 months, the moment when resistin mRNA levels are significantly higher in the epididymal and the retroperitoneal than in the inguinal and mesenteric WAT and than in the BAT. The transient increased resistin expression in the epididymal and the retroperitoneal WAT at a period of time in which there is a change in diet (from milk to chow) suggests a common nutritional regulation of the resistin gene. Circulating resistin levels increase with age probably reflecting the increase in the body fat content.
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The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively.
HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects (P < 0.001). When all subjects were considered together, a progressive age-related decline in M was observed (r = –0.665, P < 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml (P < 0.005).
EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects (P < 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects.
In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.
A well-established epidemiologic association exists between hyperinsulinemia and macrovascular disease. However, the mechanism or mechanisms by which hyperinsulinemia promotes atherogenesis is unknown. Recent evidence indicates that the adrenal steroid dehydroepiandrosterone (DHEA) exerts multiple antiatherogenic effects and also suggests that hyperinsulinemia may reduce serum DHEA and DHEA-sulfate levels by decreasing production and enhancing metabolic clearance. We advance the hypothesis that hyperinsulinemia promotes macrovascular disease in part by reducing serum DHEA and DHEA-sulfate levels and illustrate how this may be the case in two clinical conditions characterized by hyperinsulinemic insulin resistance: aging and obesity.
Dehydroepiandrosterone sulfate (DS) was measured by direct tritium RIA in longitudinal plasma specimens from 97 normal healthy male participants in the Baltimore Longitudinal Study of Aging. Fasting blood was collected at regular visits (approximately 1.5 yr apart) over an average 13 yr of adulthood (cumulative age range: 32-83 yr). DS was measured in 3-4 widely spaced specimens from each subject. A decline in DS was found in 65 (67%) subjects, 13 subjects (13%) showed no change, and increases were found in the 19 remaining subjects during the study period. A plot of individual data points revealed the same pattern we had obtained previously from a cross-sectional study of a different normal male population. A plot of DS values vs. age among subjects whose DS increased during the study also revealed an age-related decline. Thus, the longitudinal decrease in circulating DS, long inferred from cross-sectional data, is confirmed for normal men in the present study. A more detailed study of every specimen collected during the study period from 12 of the Baltimore Longitudinal Study of Aging subjects (4 whose values tended to be low, 4 whose values tended to be high, and 4 whose values were near the mean) failed to reveal any patterns of variation that could be correlated with changes in life circumstances, health status, or any other discernible factors. Hence, the wide variability seen in DS among individuals within normal populations remains unexplained.
The nature of the β-adrenoceptors (β-ARs) of the white fat cells of five mammalian species (rat, hamster, rabbit, dog and humans) was reassessed. The coexistence of at least three β-ARs on the fat cell (except human) was demonstrated. Comparative binding and lipolysis studies were performed, using recently synthesized compounds selective for the atypical β-AR of the rat brown fat cell and of the rat colon. β1- and β2-ARs have previously been identified in all the mammalian white fat cells using [125I]cyanopindolol ([125]CYP) or [3H]dihydroalprenolol. In addition to these receptors, we now demonstrated the existence of a third β-AR directly involved in adrenergic-mediated lipolysis, and identified it in the white fat cells of the most commonly studied animal species, except humans. This receptor is not detected by the classically used β-antagonist radioligands, explaining the discrepancies in reports on the nature of the β-ARs of the adipose tissue. Pharmacological delineation of the third type of β-AR-induced lipolysis showed this receptor to be rather similar to the previously proposed atypical β-AR of brown and white rat fat cells. Its pharmacological properties were clarified, using new selective full agonists and partial agonists also acting as non-selective β1/β2-antagonists. The limits of [125]CYP as a radioligand were reported and the usefulness of BRL 37344, (±)-CGP 12177 and phenylethanolaminotralines derivatives (having an atypical β-activity on intestinal motility) as major tools usable for atypical β-AR activation was demonstrated. Moreover, confirming our previous results about the nature of the β-ARs (β1 and β2-ARs) located in the fat cells of women (Mauriège et al., J. Lipid Res., 1987, 17, 156), no atypical β-AR-mediated lipolysis was identified in abdominal adipose tissue from healthy women. The possible differences and similarities between this receptor and the recently cloned β3-AR are discussed.
Computed tomography (CT) was used to study the association between adipose tissue localization and glucose tolerance in a sample of 52 premenopausal obese women aged 35.7 +/- 5.5 yr (mean +/- SD) and with a body fat of 45.9 +/- 5.5%. Body-fat mass and the body mass index (BMI) were significantly correlated with plasma glucose, insulin, and connecting peptide (C-peptide) areas after glucose (75 g) ingestion (.40 less than or equal to r less than or equal to .51, P less than .01). Trunk-fat accumulation and the size of fat cells in the abdomen displayed highly significant correlations with postglucose insulin levels. The C-peptide area was also positively correlated with abdominal fat cell size (r = .76, P less than .01) and was more closely associated with the sum of trunk skin folds (r = .59, P less than .001) than with the extremity skin folds (r = .29, P less than .05). Subcutaneous and deep-abdominal-fat areas measured by CT displayed comparable associations with the plasma insulin area (r = .44 and .49, respectively; P less than .001) but marked differences in the associations with glucose tolerance. Indeed, subcutaneous abdominal fat was not significantly correlated with the glucose area, whereas deep abdominal fat showed a significant correlation (r = .57, P less than .001) with the glucose area. Midthigh fat deposition measured by CT was not, however, correlated with plasma glucose, insulin, or C-peptide areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Dehydroepiandrosterone has previously been shown to prevent weight gain in growing lean and obese mice and rats. In the present study, lean and obese female Zucker rats were treated with either 0.6 or 1.0 percent DHEA in the diet from 8 until 14 months of age. In lean rats, 0.6 percent DHEA prevented weight gain and 1.0 percent DHEA resulted in significant weight loss compared to initial body weight. Control lean rats had a significant weight gain. Both 0.6 and 1.0 percent DHEA obese rats lost weight over the experimental period while control obese rats gained weight. Food intake of DHEA-treated obese rats was lowered compared to control obese rats but was similar to that of all lean groups. DHEA lowered serum insulin levels in both lean and obese rats relative to control groups. Both 0.6 and 1.0 percent DHEA lean rats had elevated hepatic G6PD activity compared to control lean rats. DHEA obese rats had lowered G6PD activity compared to the control obese rats. Hepatic malic enzyme was elevated by DHEA treatment in both lean and obese Zucker rats. Adipose tissue weights were lowered substantially in DHEA treated lean and obese rats versus their control groups. These data indicate that DHEA treatment in adult rats has an anti-obesity effect.
Twenty adult Sprague-Dawley outbred rats (10 male and 10 female) were fed a nonpurified diet without or containing dehydroepiandrosterone acetate (DHEA 6 g/kg diet) for 11 w. DHEA-treated animals weighed less than the controls after 6 wk and until the end of treatment. However, only the differences between male groups were statistically significant. Food intake of the DHEA-fed animals was not affected, but resting heat production was elevated for both sexes. Serum triglyceride levels and activity of hepatic glucose-6-phosphate dehydrogenase of the experimental groups were lower than controls. Analyses of body composition indicated DHEA-treated animals had proportionately less body fat and therefore more body water, protein and ash than controls. In most cases, differences in body composition were due primarily to effects of DHEA on the female animals. In a second experiment, DHEA treatment did not alter urinary ketone levels nor did it enhance citrate synthase activity in interscapular brown fat, skeletal muscle, heart or liver. Findings suggest that DHEA acetate treatment affected body weight, body composition and utilization of dietary energy by both impairing fat synthesis and promoting fat-free tissue deposition and resting heat production. Possible mechanisms by which DHEA may affect metabolism are discussed.
To clarify the mechanism responsible for age-related changes in insulin action, the euglycemic clamp technique was performed with graded doses of insulin in conscious rats aged 2, 4, 10, and 20 mo. Insulin binding (IB) to muscle membranes was also studied. Maximal response of insulin-induced glucose disappearance rate (Rd) was decreased significantly between 2 and 4 mo of age. Dose-response curves shifted to the right progressively up to 20 mo of age. However, IB to the muscle membrane diminished between 1 and 4 mo of age without a decrease thereafter. When Rd was plotted against insulin bound to the membranes, the resulting curves shifted to the right with aging, suggesting a coupling defect between the binding and effector unit. In conclusion, insulin action alters in rats between 2 and 20 mo of age. The most pronounced impairment in IB and maximal response of insulin-induced Rd occurs during early life stage (through maturation) and then a coupling defect seems to be superimposed with further aging. However, we cannot exclude the possibility that these changes may be secondary to obesity or reduced physical activity, rather than aging per se.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Several previously reported studies have shown that in rodents exogenously administered dehydroepiandrosterone (DHEA) can cause numerous metabolic changes. In the present study some additional metabolic effects of DHEA are presented using old lean and obese Zucker rats. With this experimental model most of the effects were found to occur in the obese rat. These included decreases in serum insulin and cholesterol as well as a decrease in hepatic acyl-CoA cholesterol-acyl transferase activity. In both lean and obese rats an increase in hepatic long-chain fatty acyl-CoA hydrolase was found. This increase in activity may partially explain DHEA's effect on decreasing body weight in rodents.
Dehydroepiandrosterone (DHEA), a major adrenal secretory steroid in humans, was therapeutic when fed in a concentration of 0.4% to C57BL/KsJ mice with either non-insulin-dependent or insulin-dependent diabetes. Genetically diabetic (db/db) mice of both sexes develop obesity and a glucose intolerance and hyperglycemia associated with insulin resistance by 2 mo of age, and exhibit beta-cell necrosis and islet atrophy by 4 mo. In contrast, DHEA feeding initiated between 1 and 4 mo of age, while only moderately effective in preventing obesity, did prevent the other pathogenic changes and effected a rapid remission of hyperglycemia, a preservation of beta-cell structure and function, and an increased insulin sensitivity as measured by glucose tolerance tests. DHEA feeding was also therapeutic to normal C57BL/KsJ male mice made diabetic by multiple low doses of streptozotocin (SZ). While DHEA treatments did not block either the direct cytotoxic action of SZ on beta-cells or the development of insulitis, the steroid significantly moderated the severity of the ensuing diabetes (reduced hyperglycemia and water consumption, and increased plasma insulin and numbers of residual, granulated beta-cells.
Several studies were undertaken to determine the effect of dehydroepiandrosterone (DHEA) on growth in Zucker rats. In experiment 1, 3 weeks of DHEA treatment in lean rats resulted in decreased body weight gain in comparison to control rats. In experiment 2, both lean and obese rats were treated with DHEA from 6 to 21 weeks of age. Significant decreases in body weight were found for both lean and obese DHEA-treated rats. The food efficiency ratio (FER) was significantly decreased in both DHEA-treated groups. Significant decreases in parametrial and retroperitoneal fat pads were found in both lean and obese DHEA-treated rats. This was primarily attributed to a decrease in fat cell number in lean rats and to decreases in both number and size of fat cells in obese rats. In experiment 3 obese female rats were treated with DHEA from 6 to 21 weeks of age followed by 15 weeks with DHEA removed from the diet. Significantly more weight was gained by the rats previously treated than by the control rats, but body weight remained significantly lower than in the control groups. These data indicate DHEA has an effect on altering body weight and body fat in lean and obese Zucker rats.
In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.
The effects of aging on various aspects of insulin secretion and action were studied in male Sprague-Dawley rats, maintained from 1 1/2 to 12 mo of age on conventional rat chow, sucrose-rich, or calorie-restricted diets. In chow-fed rats, islet volume increased as the animals grew from 1 1/2 to 12 mo of age, but glucose-stimulated insulin secretion (per volume islet) declined over the same interval. In addition, in vivo insulin-stimulated glucose utilization fell in these rats. However, the plasma insulin response to an oral glucose challenge was sufficient to prevent frank decompensation of glucose tolerance (presumably due to an increase in total pancreatic endocrine cell mass). All these changes, with the exception of the decline in glucose-stimulated insulin secretion per volume islet, were accentuated by feeding sucrose. Thus, 12-mo-old sucrose-fed rats had larger islets and higher plasma insulin levels in response to an oral glucose challenge, and the rats were more insulin-resistant than chow-fed rats. However, glucose-stimulated insulin release per volume islet was similar in 12-mo-old chow-fed and sucrose-fed rats. In contrast, calorie restriction led to an amelioration in all but one of the age-related changes, i.e., islets from calorie-restricted rats were comparable in size to those of 2-mo-old rats, the animals had lower plasma insulin levels in response to an oral glucose load, and they were less insulin resistant than the other two groups of 12-mo-old rats. On the other hand, glucose-stimulated insulin secretion per volume islet was similar to that of the other 12-mo-old rats. These results suggest that aging leads to marked changes in both insulin secretion and insulin action. The decline in glucose-stimulated insulin secretion per unit endocrine pancreas appears to be an inevitable consequence of the aging process. In contrast, the age-related changes in islet size, insulin response to a glucose load, and in vivo insulin-stimulated glucose uptake are extremely responsive to variations in amount and kind of calories. DIABETES 32:175-180, February 1983.
Dehydroepiandrosterone (DHEA) has been reported to exert antiglucocorticoid activity. When administered to obese, hypercorticosteronemic Zucker rats, it causes a diminution of food intake and a reduction in their rate of weight gain. This experiment was conducted to evaluate whether this biologic effect could be ascribed to chronic adrenal insufficiency. Obese and lean Zucker rats were treated with DHEA as a food supplement for 28 days. Upon sacrifice, organ weights and serum chemistries were measured, along with neurotransmitter levels in regions of the hypothalamus. Results showed that although the obese animals gained weight more slowly, had lower insulin levels, and ate less, their serum glucose, corticosterone, and ACTH levels were not different from control. Hypothalamic neurotransmitters in the obese rat were unaffected by chronic DHEA treatment. We concluded that, although DHEA clearly affects Zucker weight gain, it does not induce chronic adrenal insufficiency.
Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
Young adult male rats were treated with 4 mg dehydroepiandrosterone (DHEA)/100-g diet for 4 wk or were fed the same purified diet unadulterated (51 carbohydrate:20 fat: 23.5 protein; wt/wt). After 1 wk body weight and fat mass of the DHEA-fed rats were significantly less than the controls. By the end of week 3, fat-free mass of the DHEA rats was less than the controls. Neither food intake nor resting metabolism, measured by indirect calorimetry, was different between groups. Isolated epididymal adipocytes of DHEA rats were significantly smaller and isoproterenol (x 10(7) M) stimulation of glycerol release was 53% greater (P < 0.01) than the controls. Basal rate of glycerol release increased significantly for both groups in response to the adenosine inhibitor adenosine deaminase; there were no significant interaction effects. Inhibition of lipolysis by the adenosine analogue phenylisopropyladenosine was similar between groups. Findings support the hypothesis that DHEA reduces adiposity directly by increased lipolysis, but the mechanism of action does not involve a change in the antilipolytic function of adenosine.
The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential
role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed
and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses
of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral
effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and
energy balance.
The steroid hormone intermediate, DHEA, has been proposed as a therapeutic agent for the treatment of obesity. Its effects on lipogenesis, substrate cycling, peroxisome proliferation, mitochondrial respiration, protein synthesis, and thyroid hormone function have been reported. The results of these studies suggest that the antiobesity function of DHEA is not simply one of inhibiting fat synthesis and deposition but is one of affecting a number of pathways that contribute to the maintenance of the isoenergetic state rather than the promotion of positive energy balance.
Adipose differentiation is accompanied by changes in cellular morphology, a dramatic accumulation of intracellular lipid and activation of a specific program of gene expression. Using an mRNA differential display technique, we have isolated a novel adipose cDNA, termed adipoQ. The adipoQ cDNA encodes a polypeptide of 247 amino acids with a secretory signal sequence at the amino terminus, a collagenous region (Gly-X-Y repeats), and a globular domain. The globular domain of adipoQ shares significant homology with subunits of complement factor C1q, collagen alpha 1(X), and the brain-specific factor cerebellin. The expression of adipoQ is highly specific to adipose tissue in both mouse and rat. Expression of adipoQ is observed exclusively in mature fat cells as the stromal-vascular fraction of fat tissue does not contain adipoQ mRNA. In cultured 3T3-F442A and 3T3-L1 preadipocytes, hormone-induced differentiation dramatically increases the level of expression for adipoQ. Furthermore, the expression of adipoQ mRNA is significantly reduced in the adipose tissues from obese mice and humans. Whereas the biological function of this polypeptide is presently unknown, the tissue-specific expression of a putative secreted protein suggests that this factor may function as a novel signaling molecule for adipose tissue.
We measured plasma leptin concentrations by RIA in 204 normal weight and obese subjects, aged 18-80 yr, using full-length recombinant human leptin as a standard. Fasting levels between 1.2-97.9 ng/mL were observed. The plasma leptin concentration was highly correlated with percent body fat (r = 0.710; P < 0.0001) and was 3 times as high in women as in men (17.1 vs. 5.8 ng/mL; P < 0.0001). Circulating leptin was inversely related to age and was reduced 53% in subjects over age 60 yr. A statistical model containing percent body fat, gender, and age accounted for 65% of the variance in plasma leptin levels. Leptin was not independently related to abdominal fat distribution, plasma lipids and lipoproteins, chronic energy intake, diet composition, plasma insulin, or maximum oxygen consumption. However, plasma leptin was reduced by 26% in 5 obese subjects who consumed a 1000-Cal diet for 10 days (P = 0.004). We conclude that circulating leptin rises continuously with increasing adiposity. Gender, age, and short term caloric restriction may be important secondary regulators of plasma leptin.
Abdominal obesity has emerged as a strong and independent predictor for non-insulin dependent diabetes mellitus (NIDDM). Adiposity located centrally in the abdominal region, and particularly visceral as opposed to subcutaneous fat, is also distinctly associated with hyperlipidemia, compared with generalized distributions of body fat. These lipoprotein abnormalities are characterized by elevated very low density lipoprotein (VLDL) and low density lipoprotein (LDL) levels, small dense LDL with elevated apolipoprotein B levels, and decreased high density lipoprotein2b (HDL2b) levels. This is the same pattern seen in both familial combined hyperlipidemia and NIDDM. The pronounced hyperinsulinemia of upper-body obesity supports the overproduction of VLDL and the increased LDL turnover. We have proposed that an increase in the size of the visceral fat depot is a precursor to the increased lipolysis and elevated free fatty acid (FFA) flux and metabolism and to subsequent overexposure of hepatic and extrahepatic tissues to FFA, which then, in part, promotes aberrations in insulin actions and dynamics. The resultant changes in glucose/insulin homeostasis, lipoprotein metabolism, and vascular events then lead to metabolic morbidities such as glucose intolerance, NIDDM, dyslipidemia, and increased risk for coronary heart disease.
To determine if chronic administration of a low level of dehydroepiandrosterone-sulfate (DHEAS) (10 micrograms/ml drinking water) attenuates adiposity in male Osborne-Mendel rats fed low-fat (11% of kcals) vs high fat (46% of kcals) diets.
Rats were randomly assigned to one of four treatment groups for 6 wk in this 2 x 2 factorial study. The main effects tested were diet (low vs high fat) and DHEAS (- or +).
Male Osborne-Mendel rats (initial body wt approximately 265 g).
Adipocyte mass, size and number from two major fat depots (retroperitoneal, epididymal); mass of one subcutaneous adipose depot (inguinal); serum levels of triglycerides, insulin, glucose and DHEAS; brown adipose tissue (BAT) mass; body weight gain, food and water consumption, and residual carcass composition.
DHEAS treatment had no effect on weight gain, food consumption or water intake. DHEAS-treated rats fed the high-fat diet had smaller fat pads containing fewer adipocytes and less carcass lipid than the non DHEAS-treated rats fed the high-fat diet. In contrast, DHEAS-treated rats fed the low-fat diet had similar levels of adipose tissue mass and cellularity compared to control animals fed the low-fat diet.
Administration of a low dose of DHEAS (10 micrograms/ml or 0.8 mg/kg body wt/d) in the drinking water of young male Osborne-Mendel rats fed a high-fat diet for 6 wk reduced carcass lipid, fat depot mass and retroperitoneal and epididymal adipocyte number compared to their high-fat-fed cohorts. In this study, the antiobesity effects of DHEAS were specific to the level of dietary fat used.
Visceral obesity is frequently associated with muscle insulin resistance. Rats fed a high-fat diet rapidly develop obesity and insulin resistance. Dehydroepiandrosterone (DHEA) has been reported to protect against the development of obesity. This study tested the hypothesis that DHEA protects against the increase in visceral fat and the development of muscle insulin resistance induced by a high-fat diet in rats. Feeding rats a diet providing 50% of the energy as fat for 4 wk resulted in a twofold greater visceral fat mass and a 50% lower rate of maximally insulin-stimulated muscle 2-deoxyglucose (2-DG) uptake compared with controls. Rats fed the high-fat diet plus 0.3% DHEA were largely protected against the increase in visceral fat (+ 11.3 g in high fat vs. + 2.9 g in high fat plus DHEA, compared with controls) and against the decrease in insulin-stimulated muscle 2-DG uptake (0.94 +/- 0.15 mumol.ml-1.20 min-1, controls; 0.46 +/- 0.06 mumol.ml-1.20 min-1, high-fat diet; 0.78 +/- 0.07 mumol.ml-1.20 min-1, high fat + DHEA). DHEA did not affect food intake. These results show that DHEA has a protective effect against accumulation of visceral fat and development of muscle insulin resistance in rats fed a high-fat diet.
The obese Zucker rat has a genetically flawed leptin system and is a model of hyperphagia, obesity, hyperlipidemia, and markedly elevated leptin levels. Dehydroepiandrosterone (DHEA) administration reduces hyperphagia, hyperlipidemia, and obesity in Zucker rats. Since serum leptin levels are associated with body fat, we wondered what the effects of fat pad weight reduction from DHEA administration would have on leptin levels. This experiment investigated the effects of DHEA on intra-abdominal fat pads, serum lipids, and peripheral leptin in male lean and obese Zucker rats that were administered DHEA in their food from 4 weeks of age to 20 weeks. Lean and obese rats received plain chow or chow containing DHEA. Additional chow-fed groups of lean and obese weight-matched controls and obese pair-fed rats helped to control for the reduced body weight, food intake, and fat pad weights seen with DHEA administration. DHEA administration to lean Zucker rats reduced body weight and fat pad weights, but leptin levels showed a lower trend. Among obese rats, both DHEA treatment and pair-feeding reduced body weight and fat pad weights, but only DHEA lowered leptin levels. The weight-matched controls had reductions in fat pad weights similar to the DHEA-treated group, but with increased leptin levels. Thus, DHEA may exert a small, independent effect on leptin levels in this animal model, but the reduction is less than what would be expected.
Obesity could well become the most common health problem of the 21st century. There are more opportunities to consume large quantities of food: big portions of tasty, varied food, at reasonable prices, are available everywhere. Moreover, our bodies are better adapted to combat weight loss than to combat weight gain, since for thousands of years our species evolved in circumstances where nutrients were in short supply.
The response of each individual to diet and other environmental factors varies considerably, depending on the characteristics of his/her body weight control mechanism. The differentiating element in the future, especially as regards the dietary and pharmacological control of obesity, will be knowledge of an individual's possible response depending on his/her genetic background.
Obesity can occur as a result of genetic or acquired changes in three main types of biochemical processes, which are the main focus of this review: a) feeding control, which determines the sensations of satiety and hunger through processes that depend on a interplay between internal signals (notably leptin) and environmental factors; b) energy efficiency, in particular the activation of thermogenesis mediated by uncoupling proteins (UCPs) that makes it possible to dissipate part of the energy contained in food as heat instead of accumulating it as fat, and c) adipogenesis, the process by which cells specialised in fat storage (adipocytes) are formed, which is controlled by an interplay of transcription factors, including memebers of the C/EBP, PPARγ and ADD families.
The knowledge of a growing numbers of genes and molecules implicated in these three types of processes and of their metabolic relationships is leading toward a molecular understanding of the body weight regulatory system and is paving the way for new methods of obesity control, especially pharmacological but also nutritional and possibly involving genetic intervention.
Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way
to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform,
provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification
of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters
into the particular topics of the relative quantification in real-time RT–PCR of a target gene transcript in comparison to
a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated
only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model
needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA
integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler
PCR using the established mathematical model.
Serum leptin levels and leptin mRNA expression by adipose tissue increase with age and are mainly associated with an increase in adiposity. Regional changes in both leptin production and fat distribution contribute to circulating leptin levels and may play a role in the regulation of body weight. a capacity that changes during development. Here, we have studied leptin mRNA expression in four different white adipose tissue depots (epididymal, retroperitoneal, mesenteric, inguinal; namely, EWAT, RWAT, MWAT, IWAT) and in interscapular brown adipose tissue (IBAT). We have also studied their relationship with lipid content and adiposity changes, together with serum leptin levels in male rats at different ages (18, 55, 93, 159, 212, 294 and 355 days). Serum leptin levels increased during development, reaching stable levels at the age of 7 months, and, as expected, were highly correlated with both the adiposity index (r=0.908, P<0.01) and body weight (r=0.906, P<0.01). Leptin mRNA expression also increased with age, following characteristic ontogenic patterns in every adipose tissue depot. The patterns were similar in EWAT and RWAT: leptin expression increased very rapidly during the first 55 days for EWAT and 3 months for RWAT, with a peak in the latter at 7 months, and high expression levels were retained for the rest of the study period. In IWAT and IBAT, leptin expression increased steadily during the 12-month period studied and was significantly lower than levels in EWAT and RWAT. Leptin expression in MWAT increased progressively with age to reach levels close to those of EWAT and RWAT in 10-month-old animals. The pattern of leptin expression in both EWAT and RWAT paralleled their lipid content, and leptin mRNA expression per unit of tissue lipid content was maintained high and constant from a very young age (about 2 and 3 months, respectively). However, the expression of mRNA for leptin (expressed per unit of tissue lipid concentration) in MWAT, IWAT and IBAT increased steadily during the whole period studied, without attaining the maximal levels observed in EWAT and RWAT. MWAT, IWAT and IBAT maintained their capacity to increase leptin mRNA expression in response to an additional accumulation of lipids. Our data demonstrate that there are regional-specific differences and different rates of increase of leptin gene expression within distinct depots of WAT and BAT. These changes cannot be uniquely explained by changes in adiposity or lipid content, implying that there are regional-specific regulatory mechanisms that may depend on the attenuation with age of the beta-adrenergic inhibitory signalling pathway upon leptin expression or on other factors.