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Estrogen and Body Weight Regulation in Women: The Role of Estrogen Receptor Alpha (ER-a) on Adipocyte Lipolysis.

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Estrogen has an important role in regulation of fat metabolism. Recent studies indicated that this process occurred due to inhibition of lipolysis by external estrogen administration. However, there was limited information regarding molecular process responsible for this phenomenon. This paper was aimed to present a brief update on recent studies explaining the effect of estrogen on adipose tissue lipolysis and the molecular pathway involved in this process. It is suggested that the effect of estrogen to reduction of lipolysis was through activation of estrogen receptor alpha (ER-a) in adipose tissue. This finding is supported by the fact that mice lacking of ESR1 gene (encodes ER-a) accumulate more fat and ESR1 mRNA in human adipose tissue was inversely correlated with body mass index (BMI). Future study should be aimed to clarify the role of ER-a on lipolysis in adipose tissue during weight loss intervention. Additionally, new pharmacological or nutritional treatment with ability to modulate ER-a activity/expression could be used as a potential weight loss intervention.
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REVIEW ARTICLE
333
Acta Medica Indonesiana - e Indonesian Journal of Internal Medicine
Estrogen and Body Weight Regulation in Women: The Role
of Estrogen Receptor Alpha (ER-α) on Adipocyte Lipolysis
Harry F. Luglio
Department of Health Nutrition, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Correspondence mail:
Department of Health Nutrition, Universitas Gadjah Mada. Jl. Farmako, Sekip Utara, Yogyakarta 55281, Indonesia.
email: harryfreitag@ugm.ac.id.
ABSTRAK
Hormon estrogen memiliki peran penting dalam pengaturan metabolisme lemak. Studi terbaru menunjukan
bahwa pemberian estrogen dapat menghambat lipolisis. Meskipun demikian, informasi mengenai proses
molekuler yang terlibat pada fenomena ini masih sangat terbatas. Review ini bertujuan untuk menyajikan
informasi mengenai berbagai macam penelitian yang menghubungkan efek dari estrogen terhadap lipolisis
jaringan adiposa dan jalur molekuler yang terlibat dalam proses ini. Diperkirakan bahwa efek dari kerja estrogen
terhadap penghambatan lipolisis terjadi akibat aktivasi estrogen receptor alpha (ER-α) di jaringan adiposa.
Hal ini didukung oleh hasil penelitian yang menunjukan bahwa hewan coba yang tidak dapat mengekspresikan
gen ESR1 memiliki penumpukan lemak yang berlebihan. Sebagai tambahan, berdasarkan studi yang dilakukan
pada manusia diketahui bahwa ekspresi ESR1 di jaringan adiposa berhubungan terbalik dengan indeks massa
tubuh. Penelitian lebih lanjut diharapkan dapat menguji peran ER-α terhadap lipolysis di jaringan adiposa
terutama untuk melihat variasi respon ER-α terhadap program penurunan berat badan. Selain itu, ER-α juga
dapat digunakan sebagai target pengembangan terapi farmakologis dan nutrisional untuk penurunan berat
badan di masa depan.
Kata kunci: jaringan adiposa, estrogen, reseptor estrogen, lipolisis, obesitas, wanita.
ABSTRACT
Estrogen has an important role in regulation of fat metabolism. Recent studies indicated that this process
occurred due to inhibition of lipolysis by external estrogen administration. However, there was limited information
regarding molecular process responsible for this phenomenon. This paper was aimed to present a brief update
on recent studies explaining the effect of estrogen on adipose tissue lipolysis and the molecular pathway involved
in this process. It is suggested that the effect of estrogen to reduction of lipolysis was through activation of
estrogen receptor alpha (ER-α) in adipose tissue. This nding is supported by the fact that mice lacking of ESR1
gene (encodes ER-α) accumulate more fat and ESR1 mRNA in human adipose tissue was inversely correlated
with body mass index (BMI). Future study should be aimed to clarify the role of ER-α on lipolysis in adipose
tissue during weight loss intervention. Additionally, new pharmacological or nutritional treatment with ability
to modulate ER-α activity/expression could be used as a potential weight loss intervention.
Key words: adipose tissue, estrogen, estrogen receptor, lipolysis, obesity, woman.
Harry F. Luglio Acta Med Indones-Indones J Intern Med
334
INTRODUCTION
Obesity is an increasing pandemic that
affects humans worldwide and World Health
Organization (WHO) reported that more than 500
million people over 20 years old were obese in
2008.1 The expert panel of WHO recommends
10% weight loss for obese and overweight
individuals especially by lifestyle intervention.2
A lifestyle intervention including diet, physical
activity and behaviour modication was able
to help reducing weight loss for some obese
individuals, could not be applied to everyone.3
Furthermore, with the fact that prevalence of
obesity in 2008 doubled compared to 19801
leading to assumption that what we have done so
far to prevent and treat obesity was not successful.
It is suggested that some intrinsic factors affect
the ability obese/overweight individuals to lose
weight during a lifestyle intervention.
A growing evidence shown that lipolysis was
one of the most important factor that induces
weight loss.4 Lipolysis is initiated in adipocytes
to release fatty acids (FA) thus can be used as
the source of energy in negative energy balance.5
This process is controlled by sympathetic
nervous system (SNS) via its receptor, beta
adrenergic receptor (β-AR), and dysfunction of
this receptor is related to obesity. The role of
SNS in regulating lipolysis was revealed by an
observation that denervation of white adipose
tissue induced hypertrophy6 and electrical
stimulation of its nerve led to release of fatty
acids.7 As the mediator of SNS signals, β-AR
regulates lipolysis through sequential stimulation
of adenylyl cyclase and protein kinase A (PKA)8
via a Gs protein. The catalytic subunit of
activated PKA accesses hormone sensitive lipase
(HSL) and perilipin then induces release of fatty
acid and glycerol into circulation.9
In obese individuals, the sensitivity of
lipolysis response by β-AR was reduced. A study
by Schiffelers et al. revealed that during β2-AR
stimulation, obese subjects had lesser increment
in energy expenditure, plasma Non-esteried
fatty acid (NEFA) and glycerol level compared
to lean individuals.10 This is supported by other
evidence showing that lipolytic noradrenaline
sensitivity was reduced in obese women
compared to non-obese women.11 It was also
observed that obese women had reduction in
surface density of β2-AR.11
Investigating β-AR induced lipolysis in
obese individuals is important because weight
loss intervention was related to changes of
responsiveness to lipolysis in adipose tissue.
Various experimental studies in human shown
that a short-term (up to 4 weeks) very low calorie
diet (VLCD) was able to increase responsiveness
of adipose tissue lipolysis to stimulation.12–14
Similiar to the result, the increment of specic
β2-AR induced lipolysis was seen after long-term
(8-15 weeks) low calorie diet.15
FACTORS THAT INFLUENCE LIPOLYSIS
Because lipolysis has an important role
on lipid mobilization, this process is highly
regulated. There are some signals with the ability
to inuence lipolysis by increasing or decreasing
the process through several different pathways.
Until recently, at least 4 pathways have been
investigated.20 Chaves et al.20 reviewed that the
main pathway that induces lipolysis is the cAMP-
dependent protein kinase A (PKA) pathway.
Additionally, protein kinase B (PKB), protein
kinase C (PKC) pathway, mitogen activated
protein kinase (MAPK) pathway, guanylyl
cyclise and cyclic guanosine monophosphate
(cGMP) were also responsible in regulation on
lipolysis.21–24
Catecholamines, the SNS signals which
includes neurotransmitter norepinephrine and
hormone epinephrine, are able to stimulate
lipolysis through PKA pathway.20 When
cathecolamine binds to β-AR at the surface of
adipocyte, adenylyl cyclise is activated thus
intracellular concentration of cAMP increased.
Increasing cAMP leads to activation of PKA.
Activated PKA intracellular reacts with perilipin
1 and hormone sensitive lipase (HSL) thus
leading to activation of those proteins. In non-
stimulated condition, HSL is located at the
cytoplasm. However, the phosphorilated HSL
is able to move to lipid droplet and initiate
breakdown of triglyceride.20 (Figure 1)
There are some signals that are also able
to induce lipolysis in human adipose tissue.
Thyroid-stimulating hormone (TSH) stimulates
lipolysis using the same pathway as used
Vol 46 • Number 4 • October 2014 Estrogen and body weight regulation in women
335
by cathecolamines, the PKA pathway. This
protein binds to G-protein-coupled receptor
inducing stimulation of adenylyl cyclise thus
increases cAMP level.25 Prostaglandin E2 has
been reported to affect lipolysis with biphasic
effect. Low concentration of Prostaglandin E2
inhibits the response while high concentration
of the Prostaglandin E2 leading to stimulatory
response.26,27
Insulin is secreted by human pancreas
and has the ability to inhibit lipolysis through
PKB pathway. The signal is rstly recognized
by insulin receptors and insulin receptors
substrates. Those processes then followed by
several reactions mediated by phosphorilation
and activation of PDE3B, which decreases
cAMP levels. The decreasing level of cAMP
thus reduced PKA activity as well as HSL
phosporilation. Because less HSL is able to
translocate into lipid droplet, less lipolysis
occured in the tissue.20,28 Interestingly, a study
done by Campbell et al.29 revealed that the ability
of insulin to suppress lipolysis is impaired in
obesity. Location of white adipose tissue in
human body is also related to responsiveness to
insulin inhibition effect to lipolysis.30
ESTROGEN INHIBITS LIPOLYSIS
The relationship between estrogen and
adipose tissue metabolism has been investigated
before. Low estrogen level in menopause women
was associated with loss of subcutaneous fat
while male-to-female transsexual receiving
estrogen treatment increased subcutaneous fat.31,32
Additionally, when postmanopause women
receiving hormone replacement therapy the
epinephrine-stimulated lipolysis was inhibited.33
In line with the result, estrogen treatment in male-
to-female transsexuals was able to inhibit basal
lipolysis.34 Some human experiment studies were
done to clarify the acute effect of estrogen to
adipose tissue lipolysis. Van Pelt et al.35 showed
that estrogen can acutely reduce basal lipolysis
in postmenopause women. Estrogen has also
proven to acutely inhibit adrenaline-stimulated
lipolysis in abdominal subcutaneous adipose
tissue.36
Although various studies suggested that
lipolysis is inhibited by estrogen signal,
mechanism underneath this process is still
unclear. Pedersen et al.37 investigated the
inuence of estrogen to adrenergic receptors in
vivo from estradiol treated women and in vitro.
The receptors, including α and β adrenergic
receptors, were important proteins that initiate
lipolysis in adipose tissue. From those receptors,
only α2 adrenergic receptors that is affected by
estradiol treatment both in vivo and in vitro.37
In this study, the response of both subcutaneous
and visceral adipose tissue was also evaluated.
Interestingly, the effect of estradiol on α2
adrenergic receptors is only seen in subcutaneous
adipose tissue.37 The study showed that adipose
tissue LPL and HSL in vivo, the downstream
signal of adrenergic receptors, were not affected
by estradiol.
Estrogen receptor is a nuclear receptor family
of ligand-activated transcription factor that is
responsible for physiological action of estrogen.
This receptor is divided into 2 subtypes, estrogen
receptor α (ER-α) and estrogen receptor β (ER-
β). Those subtypes are located in different organs
in human body. ER-α is mostly expressed in
reproductive tissues, kidney, bone, white adipose
tissue, and liver, while ER-β is expressed in
the ovary, prostate, lung, gastrointestinal tract,
bladder, hematopoietic cells, and the central
nervous system (CNS).38 In order to investigate
how estrogen regulate lipolysis, Pedersen et al.37
also explored which estrogen receptor involved
in this process. In the study, they reported that the
effect of estrogen to adipose tissue was mediated
through ER-α instead of ER-β.37
Estrogen could affect cells via genomic
Insulin
Cathecolamine
Thyroid
stimulating
hormone
Prostaglandin E2
Estrogen
LIPOLYSIS
OF LIPID
DROPLET
Figure 1. Regulation of adipose tissue lipolysis
Harry F. Luglio Acta Med Indones-Indones J Intern Med
336
and non-genomic mechanism. The genomic
mechanism of estrogen is done via activation of
estrogen through direct binding of ER dimmers
to estrogen-responsive elements. This process
happened in the regulatory regions of estrogen
target genes thus transcription of the target genes
could start. On the other hand, estrogen could
also work through non-genomic mechanism.
In this process, activated ERs could activates
of several signalling cascade including protein
kinase A (PKA), protein kinase C (PKC) and
mitogen-activated protein kinase (MAPK).39
Investigations have been made to clarify
the importance of ER-α in adipose tissue
metabolism as well as its role in obesity. In an
animal study it was shown that mice lacking
of ESR1 gene, a gene that responsible for
production of ER-α, have higher amount of
adipose tissue compared to wild type.40 In
population based studies, polymorphism of ESR1
gene has been associated with BMI and waist
circumferences.41–45 The genetic expression of
ESR1 in subcutaneous adipose tissue has been
measured in premenopausal women. Nilsson et
al.43 shown that the expression of ESR1 mRNA
was inversely correlated with BMI. However,
they found no relationship with variation of that
gene with subcutaneous adipocyte lipolysis.
CONCLUSION
Although it has been shown that lipolysis is
regulated by estrogen, the mechanism underneath
this process is still unclear. Several studies
have suggested that this is due to the activation
of ER-α but until recently there is no solid
evidence to support this hypothesis. Therefore,
future study should be aimed to investigate the
role of ER-α on lipolysis in adipose tissue. The
importance of ER-α signal to affect expression
of proteins that are involved in adipose tissue
lipolysis should be addressed.
Additionally, investigation on the effect of
ER-α agonist to the sensitivity of adrenergic
receptor to insulin and norephinephrine is
potential to be done in the future. It has been
summarized that drugs or treatments targetting
on beta adrenergic activation is already approved
and used.8 Thus, new pharmacological and
nutritional treatment with ability to modulate
ER-α activity/expression could be used as a
potential weight loss intervention.
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... Catecholamines such as epinephrine and norepinephrine act on tissues through adrenergic receptors (ARs), which are split into α and ß classes, and have been shown to regulate lipolysis through the inhibition or activation of cAMP and the phosphorylation of lipolytic enzymes such as hormone-sensitive lipase [51,52]. α and ß ARs have reciprocal effects on lipolysis: ßAR's stimulate lipolysis, while αAR's are anti-lipolytic and positively correlate with an increase in adipose tissue mass [51,53,54]. ...
... Catecholamines such as epinephrine and norepinephrine act on tissues through adrenergic receptors (ARs), which are split into α and ß classes, and have been shown to regulate lipolysis through the inhibition or activation of cAMP and the phosphorylation of lipolytic enzymes such as hormone-sensitive lipase [51,52]. α and ß ARs have reciprocal effects on lipolysis: ßAR's stimulate lipolysis, while αAR's are anti-lipolytic and positively correlate with an increase in adipose tissue mass [51,53,54]. Because men and women have markedly different fat accumulation patterns, it should be noted that the relative expression of αAR and ßAR varies by adipose depot [53,54]. ...
... Taken together, differences in AR between adipose depots likely contributes to the variant lipolysis rates and distribution of adipose tissue between women and men. Interestingly, estrogen has been shown to regulate ADR expression through ERα activation [51,53,54]. In vivo and in vitro studies using human abdominal subcutaneous adipose tissue have demonstrated that ERα activation by estrogen upregulates the expression of ADRA2A [53]. ...
Article
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Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema.
... 18 It has been shown that the administration of ethinyl estradiol and progestin may increase plasma volume, and that the administration of a combination of both exogenous sex hormones causes the greatest increase. 16 Furthermore, a recent review concluded that ethinyl estradiol administration could inhibit the lipolysis process, 19 thereby affecting fat mass (FM) and FFM. These findings suggest that there may be differences in BC variables throughout an OC cycle between the APP and the WP. ...
... For our participants taking OC, no differences in body mass, FM, FFM, BM, BMI, and TBW between the OC phases (WP and APP) were reported in the present study. These findings are not in line with earlier literature that found an increase of plasma volume 16 and an inhibition of the lipolysis process 19 with the administration of ethinyl estradiol and progestin. This may be explained by the low dosages of exogenous sex hormones that monophasic OC pills contain nowadays, which may not be high enough to affect the physiological processes in well-trained females. ...
Purpose: The influence of female sex hormones on body fluid regulation and metabolism homeostasis has been widely studied. However, it remains unclear whether hormone fluctuations throughout the menstrual cycle (MC) and with oral contraceptive (OC) use affect body composition (BC). Thus, the aim of this study was to investigate BC over the MC and OC cycle in well-trained females. Methods: A total of 52 eumenorrheic and 33 monophasic OC-taking well-trained females participated in this study. Several BC variables were measured through bioelectrical impedance analysis 3 times in the eumenorrheic group (early follicular phase, late follicular phase, and midluteal phase) and on 2 occasions in the OC group (withdrawal phase and active pill phase). Results: Mixed linear model tests reported no significant differences in the BC variables (body weight, body mass index, basal metabolism, fat mass, fat-free mass, and total body water) between the MC phases or between the OC phases (P > .05 for all comparisons). Trivial and small effect sizes were found for all BC variables when comparing the MC phases in eumenorrheic females, as well as for the OC cycle phases. Conclusions: According to the results, sex hormone fluctuations throughout the menstrual and OC cycle do not influence BC variables measured by bioelectrical impedance in well-trained females. Therefore, it seems that bioimpedance analysis can be conducted at any moment of the cycle, both for eumenorrheic women and women using OC.
... Pinpointing what factors protect female adipose tissue prior to menopause could have tremendous implications for women's health. In this regard, the protection against adipose tissue dysfunction is likely due to adipocyte-specific estrogen signaling (D'Eon et al., 2005;Mauvais-Jarvis et al., 2013;Kim et al., 2014;Luglio, 2014) through estrogen receptor alpha (ERα) (Davis et al., 2013). Signaling through this steroid receptor has been shown to increase mitochondrial function and biogenesis in adipose tissue (Klinge, 2008), consistent with a signature profile of healthy adipose tissue 'immunometabolism' . ...
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Metabolic disease risk escalates following menopause. The mechanism is not fully known, but likely involves reduced signaling through estrogen receptor alpha (ERα), which is highly expressed in brown and white adipose tissue (BAT and WAT). Objective: Test the hypothesis that uncoupling protein (UCP1) activation mitigates metabolic dysfunction caused by loss of signaling through ERα. Methods: At 8 weeks of age, female ERα knock out (KO) and wild-type mice were housed at 28°C and fed a Western-style high-fat, high sucrose diet (HFD) or a normal low-fat chow diet (NC) for 10 weeks. During the final 2 weeks, they received daily injections of CL 316,256 (CL), a selective β3 adrenergic agonist, or vehicle control (CTRL), creating eight groups: WT-CTRL, WT-CL, KO-CTRL, and KO-CL on HFD or NC; n = 4–10/group. Results: ERαKO demonstrated exacerbated HFD-induced adiposity gain (P < 0.001) and insulin resistance (P = 0.006). CL treatment improved insulin sensitivity (P < 0.05) and normalized ERαKO-induced adiposity increase (P < 0.05). In both genotypes, CL increased resting energy expenditure (P < 0.05) and induced WAT beiging indicated by increased UCP1 protein in both perigonadal (PGAT) and subcutaneous (SQAT) depots. These effects were attenuated under HFD conditions (P < 0.05). In KO, CL reduced HFD energy consumption compared to CTRL (P < 0.05). Remarkably, CL increased WAT ERβ protein levels of both WT and KO (P < 0.001), revealing CL-mediated changes in estrogen signaling may have protective metabolic effects. Conclusion: CL completely restored metabolic dysfunction in ERαKO mice. Thus, UCP1 may be a therapeutic target for treating metabolic dysfunction following loss of estrogen receptor signaling.
... The reason that men tended to have larger ORs of BMI for chronic diseases might be ascribed to the great differences in the diet and habits between genders, for example, men tended to smoke, drink (Tables 1 and 3) and eat more meat 23,24 . Another possible explanation was the differences in body function, e.g., estrogen was believed to play an important role in fat metabolism regulation, and to restrain fat accumulated in waist [25][26][27] . This might be the reason for such significant difference in dyslipidemia between males and females, since estrogen might help females to decline the risk of BMI towards dyslipidemia. ...
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High body mass index (BMI) predisposes to several chronic diseases, but a large-scale systematic and detailed study of dose-response relationship between BMI and chronic diseases has not been reported previously. In this study, we aimed to investigate the relationship between BMI and 3 chronic diseases (hypertension, dyslipidemia and MetS) in northeast China. A sample of 16412 participants aged 18~79 years old were included in Jilin province in 2012. The lambda-mu-sigma (LMS) method was applied to examine the trend of BMI by age, and the restricted cubic splines were used to investigate the non-linear associations (dose-response curve) between BMI and chronic diseases. It was pointed out that BMI increased rapidly when young, then kept steady in middle age, and finally declined slowly in old age, and accordingly age was divided into 3 segments, which were different by gender. The odds ratios (ORs) of BMI for the chronic diseases increased relatively slowly when young, then increased dramatically in middle-age and old population, especially for men. Further, the ORs of BMI among non-smokers were lower than those among smokers, and the same trend was shown to be more apparent among drinkers and non-drinkers. The risk of BMI for common chronic diseases increased dramatically in middle-aged, especially for men with drinking and smoking habits.
... However, increased serum AFP level was coexisted with fatty liver (Xu et al., 2014). Plus, there have been many studies presenting the relationship between ER and obesity, or adipocyte responses (Luglio, 2014;Miao et al., 2016;Pedram et al., 2016;Strong et al., 2015;Zhu et al., 2016). Therefore, it might be observed that those previous studies suggest the possible relationship, between the level of ZFHX3 and obesity. ...
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The aim of this study is to investigate whether single nucleotide polymorphisms (SNPs) of zinc finger homeobox 3 (ZFHX3 ) gene are susceptibility to obesity. Recently, several study suggested that specific polymorphisms in various genes may have effect to obesity. In present study, 54 SNPs of ZFHX3 gene were genotyped in 209 overweight and obese patients with a body mass index (BMI)≥23 kg/m² (mean±standard deviation, 44.7±6.4 kg/m²) and 159 healthy controls with a BMI of 18.5–23.0 kg/m² (43.6±6.2 kg/m²). Genotyping of each SNP was performed by custom DNA chip. Logistic regression models (dominant, recessive, and log-additive models) were used to calculate odds ratio, 95% confidence interval, and P-values. Significant association was considered at P<0.05. Among tested SNPs in ZFHX3 genes, seven SNPs of ZFHX3 gene showed significant association with obesity (P<0.05 in each model, respectively). In conclusion, these results indicate that SNPs of ZFHX3 gene might be contributed to development of obesity in the Korean population.
... Stimulation of ERα in adipose tissue affects metabolic activity of adipocytes. In general, ERα receptors are involved in the beneficial effect of estrogens on adipose tissue distribution, glucose metabolism, and inflammation [6]. However, fat tissue metabolism is in fact regulated primarily by the adrenergic system. ...
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Numerous concerns about menopause exist among women, and fear of an increase in body weight is one of the most important of them. This paper presents an overview of current knowledge concerning the etiology of obesity related to menopause and about the mechanisms of its development, with particular regard to the hormonal changes that occur during this period of life. The role of estrogens in the regulation of energy balance and the effect of sex hormones on metabolism of adipose tissue and other organs are presented. The consequence of the sharp decline in the secretion of estrogens with subsequent relative hyperandrogenemia is briefly discussed. The main intention of this review is to clarify what is inevitable and what perhaps results from negligence and unhealthy lifestyles. In the last part of the paper the possibilities of counteracting the progress of adverse changes in body composition, by promoting beneficial lifestyle modifications and the use of hormonal substitution treatment, in cases where it is reasonable and possible, are described.
... Although the beneficial effects of estrogens on adipose and cholesterol metabolism as well as on the cardiovascular system have been demonstrated, data on the receptor or receptors that mediate these positive effects have been conflicting (17)(18)(19). The sexually dimorphic anatomy of BAT in females supports the hypothesis that estrogens might be responsible for synthesizing BAT or for converting WAT to BAT (20). ...
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Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands. Estrogen receptor β (ER-β) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-β-selective ligand increased markers of tricarboxylic acid-dependent and -independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-β ligand were not observed in ER-β knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-β-selective ligand. These data highlight a new role for ER-β in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.-Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue.
Chapter
Adipose tissue is an essential body organ that is profoundly affected by both exercise and female sex hormones. As the body’s major energy reservoir, adipose tissue is extremely sensitive to exercise. That is, exercise-mediated increases in circulating catecholamines are a major stimulus for adipocyte lipolysis, the process that allows for mobilization of the lipid stored in adipose tissue for use by other cells of the body. A major physiological and anatomical difference between sexes is that females have significantly more relative adipose tissue. This important difference is clearly mediated by female sex hormones (e.g., estrogen), which dictate body fat distribution patterns, and appear to also affect the physiological function of adipose tissue. For example, ovary-intact female adipose tissue appears to be more metabolically active and less susceptible to insulin resistance and inflammation compared to that from age-matched males. There are also important differences between males and females in brown adipose tissue (BAT) metabolism, such that females have more relative BAT than males and BAT from females appears more active. It is likely that the female hormone, estrogen plays a large role in those sex differences and estrogen receptor alpha appears to mediate those effects. Finally, there are many interesting similarities between how exercise and estrogen affect the function of adipose tissue. The purpose of this chapter is to provide the reader with a basic understanding of the how exercise and estrogen affect adipose tissue physiology and function; this is done via a comprehensive overview of the most recent scientific literature on this topic.
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The aim of this study was to elucidate the roles of the b1- and the b2-adrenoceptors in thermogenesis and lipid utilization in obesity. The b1-adrenoceptor study was performed in 9 obese and 10 lean men and consisted of 4 30-min periods during which subjects received consecutive infusions of 0, 3, 6, and 9 mg/kg fat-free mass (FFM)zmin dobutamine. Energy expenditure, lipid oxidation, and plasma non- esterified fatty acids and glycerol concentrations increased similarly in both groups during b1-adrenergic stimulation. The b2-adrenoceptor study was performed in 10 obese and 11 lean men and involved 3 45-min periods during which 0, 50, and 100 ng/kg FFMzmin salbu- tamol were given in combination 1.2 mg/kg FFMzmin atenolol (bolus, 50 mg/kg FFM). During b2-adrenergic stimulation, the increases in energy expenditure and plasma nonesterified fatty acids and glycerol concentrations were reduced in the obese group. Furthermore, lipid oxidation significantly increased in the normal weight group, but remained similar in the overweight group. In conclusion, these data suggest that b1-adrenoceptor-mediated metabolic processes are sim- ilar in both groups, but b2-adrenoceptor-mediated increases in ther- mogenesis and lipid utilization are impaired in the obese. (J Clin Endocrinol Metab 86: 2191-2199, 2001)
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Hormonally stimulated lipolysis occurs by activation of cyclic AMP-dependent protein kinase (PKA) which phosphorylates hormone-sensitive lipase (HSL) and increases adipocyte lipolysis. Evidence suggests that catecholamines not only can activate PKA, but also the mitogen-activated protein kinase pathway and extracellular signal-regulated kinase (ERK). We now demonstrate that two different inhibitors of MEK, the upstream activator of ERK, block catecholamine- and β3-stimulated lipolysis by ∼30%. Furthermore, treatment of adipocytes with dioctanoylglycerol, which activates ERK, increases lipolysis, although MEK inhibitors decrease dioctanoylglycerol-stimulated activation of lipolysis. Using a tamoxifen regulatable Raf system expressed in 3T3-L1 preadipocytes, exposure to tamoxifen causes a 14-fold activation of ERK within 15–30 min and results in ∼2-fold increase in HSL activity. In addition, when differentiated 3T3-L1 cells expressing the regulatable Raf were exposed to tamoxifen, a 2-fold increase in lipolysis is observed. HSL is a substrate of activated ERK and site-directed mutagenesis of putative ERK consensus phosphorylation sites in HSL identified Ser600 as the site phosphorylated by active ERK. When S600A HSL was expressed in 3T3-L1 cells expressing the regulatable Raf, tamoxifen treatment fails to increase its activity. Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser600 and increasing the activity of HSL.
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Estradiol (E(2)) promotes and maintains the female phenotype characterized by subcutaneous fat accumulation. There is evidence to suggest that this effect is due to increased anti-lipolytic α2A-adrenergic receptors, but whether this requires long-term exposure to E(2) or is an immediate effect is not clear. To study acute effects of a single dose (4 mg) of 17β-E(2) on regional and systemic lipolysis. SIXTEEN POSTMENOPAUSAL WOMEN (AGE, 595 YEARS; WEIGHT, 6710KG; AND BMI, 24.82.9) WERE STUDIED IN A CROSSOVER DESIGN: i) placebo and ii) 4 mg E(2). Basal and adrenaline-stimulated regional lipolysis was assessed by microdialysis and substrate oxidation rates by indirect calorimetry. Tissue biopsies were obtained to assess lipoprotein lipase activity and mRNA expression of adrenergic, estrogen, cytokine, and vascular reactivity receptors. Acute E(2) stimulation significantly attenuated catecholamine-stimulated lipolysis in femoral subcutaneous adipose tissue (interstitial glycerol concentration (micromole/liter) ANOVA time vs treatment interaction, P=0.01) and lipolysis in general in abdominal adipose tissue (ANOVA treatment alone, P<0.05). E(2) also reduced basal lipid oxidation ((mg/kg per min) placebo, 0.58±0.06 vs E(2), 0.45±0.03; P=0.03) and induced a significantly higher expression of anti-lipolytic α2A-adrenergic receptor mRNA (P=0.02) in skeletal muscle tissue as well as an upregulation of eNOS (NOS3) mRNA (P=0.02). E(2) acutely attenuates the lipolytic response to catecholamines in subcutaneous adipose tissue, shifts muscular adrenergic receptor mRNA toward anti-lipolytic α2A-receptors, decreases whole body lipid oxidation, and enhances expression of markers of vascular reactivity.
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Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that "lipolytic signaling" is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
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Adipose tissue is the only tissue capable of hydrolyzing its stores of triacylglycerol (TAG) and of mobilizing fatty acids and glycerol in the bloodstream so that they can be used by other tissues. The full hydrolysis of TAG depends on the activity of three enzymes, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase, each of which possesses a distinct regulatory mechanism. Although more is known about HSL than about the other two enzymes, it has recently been shown that HLS and ATGL can be activated simultaneously, such that the mechanism that enables HSL to access the surface of lipid droplets also permits the stimulation of ATGL. The classical pathway of lipolysis activation in adipocytes is cAMP-dependent. The production of cAMP is modulated by G-protein-coupled receptors of the Gs/Gi family and cAMP degradation is regulated by phosphodiesterase. However, other pathways that activate TAG hydrolysis are currently under investigation. Lipolysis can also be started by G-protein-coupled receptors of the Gq family, through molecular mechanisms that involve phospholipase C, calmodulin and protein kinase C. There is also evidence that increased lipolytic activity in adipocytes occurs after stimulation of the mitogen-activated protein kinase pathway or after cGMP accumulation and activation of protein kinase G. Several agents contribute to the control of lipolysis in adipocytes by modulating the activity of HSL and ATGL. In this review, we have summarized the signalling pathways activated by several agents involved in the regulation of TAG hydrolysis in adipocytes.
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Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs, is a unique function of white adipose tissue. Lipolysis in adipocytes occurs at the surface of cytosolic lipid droplets, which have recently gained much attention as dynamic organelles integral to lipid metabolism. Desnutrin/ATGL is now established as a bona fide TAG hydrolase and mutations in human desnutrin/ATGL/PNPLA2, as well as in its activator, comparative gene identification 58, are associated with Neutral Lipid Storage Disease. Furthermore, recent identification of AdPLA as the major adipose phospholipase A(2), has led to the discovery of a dominant autocrine/paracrine regulation of lipolysis through PGE(2). Here, we review emerging concepts in the key players in lipolysis and the regulation of this process. We also examine recent findings in mouse models and humans with alterations/mutations in genes involved in lipolysis and discuss activation of lipolysis in adipocytes as a potential therapeutic target.
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Upper-body obesity is an important risk factor for developing non-insulin dependent diabetes. To investigate the possibility that a lipolysis defect is present in this form of obesity, we examined the adrenergic regulation of lipolysis in abdominal subcutaneous fat cells from 25 women with upper-body obesity and 24 non-obese women. Lipolytic noradrenaline sensitivity (but not the maximum rate of lipolysis) was reduced by 10-fold in obese women (p<0.01). The noradrenaline resistance could be ascribed to a 10-fold decrease in lipolytic beta2-adrenoceptor sensitivity (p<0.01). The lipolytic sensitivity of beta1- and alpha2-adrenergic receptors was normal in the obese women. A 70 % reduction in the cell surface density of beta2-adrenoceptors was observed compared to the control subjects (p<0.01). However, beta1-receptor density as well as steady-state mRNA levels for beta1- and beta2-receptors were normal in obese women. Lipolytic noradrenaline sensitivity correlated inversely with BMI (adjusted r2=0.76 together with fat cell volume in stepwise regression analysis). The fasting plasma level of free cortisol was 30 % lower in obese compared to non-obese women (p<0.05) but obesity did not influence resting plasma catecholamine levels. Thus, lipolytic catecholamine resistance is present in abdominal obesity, due to low density of beta2-adrenoceptors, which in its turn may be caused by a post-transcriptional defect in beta2-receptor expression. Whether abnormalities in circulating free cortisol levels have caused the impaired lipolytic function of these receptors in upper-body obesity remains to be established.
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The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic β cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.
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