review article estrogen deficiency and the origin of obesity …downloads.hindawi.com › journals...

Review ArticleEstrogen Deficiency and the Origin ofObesity during Menopause

Fernando Lizcano12 and Guillermo Guzmaacuten1

1 Biomedical Research Center Universidad de La Sabana (CIBUS) km 7 Autopista Norte de Bogota Chia Colombia2 Fundacion Cardio-Infantil Instituto de Cardiologia Bogota Colombia

Correspondence should be addressed to Fernando Lizcano fernandolizcanounisabanaeduco

Received 21 April 2013 Revised 3 January 2014 Accepted 6 January 2014 Published 6 March 2014

Academic Editor George Perry

Copyright copy 2014 F Lizcano and G Guzman This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Sex hormones strongly influence body fat distribution and adipocyte differentiation Estrogens and testosterone differentially affectadipocyte physiology but the importance of estrogens in the development of metabolic diseases during menopause is disputedEstrogens and estrogen receptors regulate various aspects of glucose and lipid metabolism Disturbances of this metabolic signallead to the development of metabolic syndrome and a higher cardiovascular risk in women The absence of estrogens is a cluefactor in the onset of cardiovascular disease during the menopausal period which is characterized by lipid profile variations andpredominant abdominal fat accumulation However influence of the absence of these hormones and its relationship to higherobesity in women during menopause are not clear This systematic review discusses of the role of estrogens and estrogen receptorsin adipocyte differentiation and its control by the central nervous systemn and the possible role of estrogen-like compounds andendocrine disruptors chemicals are discussed Finally the interaction between the decrease in estrogen secretion and the prevalenceof obesity in menopausal women is examined We will consider if the absence of estrogens have a significant effect of obesity inmenopausal women

1 Introduction

Obesity and obesity-related disorders such as diabetes mel-litus type 2 (DM type 2) cardiovascular disease and hyper-tension are worldwide epidemics with a greater percentageof increase in developing countries [1ndash3] Many genetic andepigenetic factors determine the pathophysiology of body fataccumulation [4 5] The majority of these factors can beclassified into different categories [6ndash9] such as (1) factorsresponsible for the hormonal regulation of appetite andsatiety (2) factors that regulate body glucose levels [10ndash12](3) regulators of basal metabolic rate [13 14] (4) factorsthat control the quantity disposition and distribution offat cells [15 16] (5) modulators for the differentiation ofprogenitor cells [17 18] and (6) those factors that determineadipocyte cell lineage [19 20] Adipocytes may also regulatethe production of cytokines that control the satiety andhunger centers in the central nervous system and modulateenergy expenditure in other tissues [21ndash23]

The increases in overweight and obesity in menopausalwomen are important public health concerns [24 25] Theprevalence of obesity which is closely associated with car-diovascular risk increases significantly in American womenafter they reach age 40 the prevalence reaches 65 between40 and 59 years and 738 in women over age 60 [26]Unfortunately there are a limited number of drugs fortreatment of obesity because the majority of new productshave been recalled due to side effects [27ndash29]

The reasons for increasing obesity in menopausal womenare not clear Some researcher arguments that the absenceof estrogens may be an important obesity-triggering factor[30] Estrogens deficiency enhances metabolic dysfunctionpredisposing to DM type 2 the metabolic syndrome andcardiovascular diseases [31 32] As a result of increases oflife expectancy in developed countries many women willspend the second half of their lives in a state of estrogendeficiency Thus the contribution of estrogen deficiency inthe pathobiology of multiple chronic diseases in women is

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 757461 11 pageshttpdxdoiorg1011552014757461

2 BioMed Research International

emerging as a conceivable therapeutic challenge of the 21stcentury However environmental epigenetic factors may alsocontribute to obesity and a cultural bias that also hinderswomenrsquos efforts to combat obesity [33 34] Perhaps it is acombination of the aforementioned factors but the triggersfor obesity require further investigation To address thisgrowing problem improved understanding of how estrogenscontribute to energy balance lipid and glucose homeostasispromises to open a novel therapeutic applications for anincreasing large segment of the female populationThepoten-tial therapeutic relevance of estrogen physiology estrogenreceptors and the estrogen pathway will be discussed in thismanuscript

2 Methods

The study design was a review of existing published originalpapers and reviews We conducted this review of SSBs andhealth outcomes in accordance with the Preferred ReportingItems for Systematic Reviews and Meta-Analysis Statement(PRISMA) [35] PubMed publications until Nov 30 2013were taken into account

3 Estrogens and Estrogen Receptorsin Fat Metabolism

The hormones help integrate metabolic interaction amongmajor organs that are essential for metabolically intensiveactivities like reproduction and metabolic function Sexsteroids are required to regulate adipocyte metabolism andalso influence the sex-specific remodeling of particular adi-pose depots [36 37] In humans the factors that controlfat distribution are partially determined by sex hormonesconcentrations [38] Men on average have less total bodyfat but more centralintra-abdominal adipose tissue whereaswomen tend to have more total fat that favors glutealfemoraland subcutaneous depots [39] Weight and fat abdominaldistribution differ among women of reproductive age andmenopausal women [40 41] The decrease in estrogen levelsin menopausal women is associated with the loss of sub-cutaneous fat and an increase in abdominal fat [42] Theimportance of estrogens in subcutaneous fat accumulationis evident in fact estrogen hormonal therapy in men alsoincreases the amount of subcutaneous fat [43 44]

In humans 17-120573-estradiol (E2) is themost potent estrogenfollowed by estrone (E1) and estriol (E3) [45] The expressionof genes that encode the enzymes in estrogen syntheticpathway such as aromatase and reductive 17120573-hydroxysteroiddehydrogenases (17120573-HSD) is critical for E2 formation [46]Protein products of several genes with overlapping functionsmay confer reductive 17120573-HSD activities in peripheral tissues[47]

Estrogens function is mediated by nuclear receptors thatare transcription factors that belong to the superfamily ofnuclear receptors Two types of estrogen receptors (ERs) havebeen identified the alpha (ER120572) and beta (ER120573) receptors[48 49] The classical genomic action mechanism of ERaction typically occurs within hours leading to activation or

repression of target genes In this classical signaling pathwayligand activated ER dissociates from its chaperone heat-shock protein and binds as a dimer directly to an estrogenresponse element (ERE) in the promoter of target genes [50ndash52] although it was considered that the action of E2 wassubject to an action in gene expression regulation Recentlythere is increasing evidence of nonnuclear cytosolic or plasmamembrane-associate receptors that mediate nongenomic andrapid effects of several steroid hormones [53ndash55] In thismanner the traditional estrogen nuclear receptors have beenfound to function outside of the nucleus to direct nonge-nomic effects [56]

Several mechanisms of membrane-signaling activationcan explain rapid responses to E2These rapid actions includeactivation of kinase phosphatase and phospholipase thatcan mediate calcium-dependent signaling and can mediatedownstream nongenomic physiological responses such aseffects on cell cycle cell survival and energy metabolism[57 58]

Human subcutaneous and visceral adipose tissues expressboth ER120572 and ER120573 [59 60] whereas only ER120572 mRNAhas been identified in Brown adipose tissue [61 62] ER120572plays a major role in the activity of adipocytes and sexualdimorphism of fat distribution Female and male mice thatlack ER120572 have central obesity have severe insulin resistanceand are diabetic [63ndash65] Although not all studies are inagreement polymorphism of ER120572 in humans have beenassociated with risk factors for cardiovascular diseases [66]

Lipolysis in humans is controlled primarily by the actionof 120573-adrenergic receptors (lipolytic) and 1205722A-adrenergicreceptors (antilipolytic) [67] Estrogen seems to promote andmaintain the typical female type of fat distribution that ischaracterized by accumulation of adipose tissue especially inthe subcutaneous fat depot with only modest accumulationof intra-abdominal adipose tissue [68] Estradiol directlyincreases the number of antilipolytic 1205722A-adrenergic recep-tors in subcutaneous adipocytes [69] Visceral adipocytesexhibit a high 1205722A120573 ratio and these cells are stimulatedby epinephrine in contrast no effect of estrogen on 1205722A-adrenergic receptor mRNA expression was observed inadipocytes from the intra-abdominal fat depot [70]Howeverit is important to highlight that the effects of estrogensdiffers on the route of administration and the lipolyticinfluence of estrogens on fat accumulation affects specificregions of the body [71ndash73] E2 may also increase betaadrenoreceptor expression through ER120572 [74] These resultsprovide a mechanism insight for the effect of E2 on themaintenance of fat distributionwith an increased use of lipidsas energy source which partially promotes fat reduction inabdominal fat This effect occurs via the facilitation of fatoxidation in the muscle by the inhibition of lipogenesis inthe liver and muscle through the regulation of peroxisomeproliferator-activated receptor 120574 (PPAR120574) and an increase inLPL expression [75ndash77] E2 also increases muscle oxidativecapacity by means of the regulation of acyl-CoA oxidase anduncoupling proteins (UCP2-UCP3) which enhances fattyacid uptakewithout lipid accumulation [78 79]Therefore E2improves fat oxidation through the phosphorylation of AMP-kinase (AMPK) in muscle and myotubes in culture [80 81]

BioMed Research International 3

ER120572

ER120572

ER120572

120573-AR

(SREBP1c)Lipolysis

LCFA

Adipogenesis

E2Epinephrine

LPLE2

UCP1

E2

PGC1-120572

AMPk-P

Figure 1 Estrogen in the fat cell (a) In brown adipocyte cell the ER alpha receptor can increase the expression of UCP1 by increasingPGC1alpha coactivator through AMPk and by a direct effect on the receptor coactivator (b) In white adipocyte ER alpha receptor activationby estrogen reduces lipoprotein lipase and increases beta-adrenergic receptor activity UCP1 uncoupling protein 1 PGC1alpha peroxisomeproliferative activated receptor gamma coactivator 1 alpha ER estrogen receptor AMPk AMP-activated protein kinase LPL lipoproteinlipase 120573-AR adrenergic receptor beta

and malonyl-CoA inactivation by increasing the affinity ofcarnitine palmitoyltransferase [82] (Figure 1)

4 Estrogens Control of Central Nucleus ofAppetite and Satiety

The hypothalamus is an important center in the brainfor the coordination of food consumption body weighthomeostasis and energy expenditure [83ndash85] Some areasof the hypothalamus including the ventromedial (VMN)arcuate (ARC) and paraventricular (PVN) nuclei regulatephysiological events that control weight [86] The processby which estrogens regulate the activity of the hypothalamicnuclei is complex [87 88] Estrogens directly and indirectlymodulate the activity of molecules involved in orexigenicaction which induces an increase in food intake [89 90]However estrogen receptors regulate the neuronal activity ofenergy homeostasis and reproductive behaviors in a differentmodeWhile ER120572 is abundantly expressed in the rodent brainin VMNandARC PVN and themedial preoptic area ER120573 isfound in the same hypothalamic nuclei but ER120573 expressionis significantly lower relative to ER120572 [88 91] POMC neuronswithin the ARC modulate food intake energy expenditureand reproduction ARC POMC ER120572 mRNA levels fluctuateover the course of the estrous cycle with the most dramaticincrease on the day of proestrus when E2 concentrationis highest [92] Estrogens directly act on POMC neuronsand regulate their cellular activity Recent findings provideadditional support for the importance of ER120572POMCneuronsand the suppression of food intake Indeed deletion of ERin POMC neurons in mice leads to hyperphagia withoutdirectly influencing energy expenditure or adipose tissuedistribution [88] Neuropeptide Y (NPY) is a potent orex-igenic that increases food intake during fasting conditions

and following food consumption by acting primarily on theARC and PVN in the hypothalamus [93] NPY exhibitsdecrease orexigenic activity after exposure to estrogens Thisinhibitory action is due to the estrogen modulation of NPYmRNA expression and receptor activity [93 94] Ghrelinpeptide is produced by parietal cells in the stomach andit regulates feeding behaviors by sensing carbohydrate andlipid levels via stimulation of the growth hormone receptorGhrelin production is not limited to the stomach differentparts of the brain and some areas of the hypothalamussuch as the ARC and PVN nuclei also produce ghrelinGhrelin antagonizes leptin action through the activationof hypothalamic neuropeptide YY1 receptor pathway aug-mented NPY gene expression and increases food intake[95ndash97] Estrogen hormone replacement therapy induces adecrease or no change in ghrelin activity [98] Melanin-concentrating hormone (MCH) promotes food consumptionby acting directly on the lateral nucleus of the hypothalamusNerves that stimulate the MCH activity arise from the ARCnucleus and contain POMCNPY andAgouti-related protein(AgRP) [99ndash101] The orexigenic effect of MCH is reduced inovariectomized rats treated with estradiol [102 103] whichis likely a direct effect of the reduced affinity of the MCHreceptor or the reduced expression ofMCHmRNA [104 105](Figure 2)

5 Estrogen and Energy Regulation

E2 administered to ovariectomized (OVX) mice fed with ahigh-fat diet preserved improve glucose tolerance and insulinsensitivity in WT but not in ER120572 minusminus mice suggesting thattargeting of the ER120572 could represent a strategy to reducethe impact of high-fat diet induced in type 2 DM [106ndash108]Insulin resistance is a central disorder in the pathogenesis


Reduce food intake

Increase energy expenditureReduce visceral adiposity

POMC VMHSF-1

HypothalamusER120572

HO

OH

Figure 2 Estrogen hypothalamic control of obesity ER alpha in thebrain regulates body weight in bothmales and females 998835 ER alpha infemale SF1 neurons regulates energy expenditure and fat distribution998835 ER alpha in female POMC neurons regulates food intake POMCproopiomelanocortin SF1 steroidogenic factor-1

of type 2DM and also a feature observed in metabolic syn-drome Excess accumulation of adipose tissue in the centralregion of the body (intra-abdominal ldquoandroidrdquo or male-pattern obesity) correlates with increased risk of and mor-tality from metabolic disorders including type 2DM [109]As women enter menopause there is a decline in circulat-ing estrogen This is accompanied by alterations in energyhomeostasis that result in increases in intra-abdominalbody fat OVX rats which are induced to exhibit obe-sity regain normal weight after estrogen replacement [36110] Although OVX induces a transient increase in foodintake [111] hyperphagia does not fully account for changesin metabolism and development obesity after OVX [112]Estrogens regulate glucoseenergy metabolism via the directand indirect control of the expression of enzymes thatare involved in this process such as hexokinase (HK)phosphoglucoisomerase (PGI) phosphofructokinase (PFK)aldolase (AD) glyceraldehyde 3-phosphate dehydrogenase(GAPD) phosphoglycerate kinase (PK) 6-phosphofructo 2-kinase fructose 26-bisphosphatase and glucose transportersGlut 3 and Glut 4 [79 113ndash115] Estrogens also increasethe activity of several enzymes in the tricarboxylic acidcycle including citrate synthase mitochondrial aconitase 2isocitrate dehydrogenase and succinate dehydrogenase [82116 117] (Figure 3)

Lipoprotein lipase (LPL) is a key-regulating enzyme forenergy metabolism that breaks down plasma triglycerides

TCA cycle

Fatty acids Pyruvate

Acetyl-CoA

Citrate synthase

Aconitase

Isocitratedehydrogenase

Alpha-ketoglutaratedehydrogenaseSuccinate

thiokinase

Succinatedehydrogenase

Fumarase

Malatedehydrogenase

Figure 3 Estradiol availability affects the regulation of enzymesinvolved in tricarboxylic acid cycle activity E2 enhances the glyco-lyticpyruvateacetyl-CoA pathway to generate electrons requiredfor oxidative phosphorylation and ATP generation to sustain uti-lization of glucose as the primary fuel source

into free fatty acids and glycerol Estradiol modulates theactivity of LPL wherein the promoter region contains estro-gen response elements that interactwith the estrogen receptorand inhibit mRNA expression in 3T3 cells and patients whoare undergoing therapy with estradiol patches [118 119] Therole of estrogens in mitochondria which generate morethan 90 of cellular ATP must also be recognized Themitochondria play an important role in the regulation ofcell survival and apoptosis and the respiratory chain isthe primary structural and functional component that isinfluenced by estrogen activity [61] The protective effect ofestrogen on oxidative stress is mediated by translocation forspecific enzymes from cytosol that prevent mitochondrialADN of oxidative attack by free radicals [120]

Brown adipose (BAT) tissue is metabolically more activethan white adipose tissue and its distribution changes withage This adipose tissue is located in the neck thorax andmajor vessels in human neonates but it is largely replacedby white adipose tissue in adults which reaches the sub-cutaneous layers between muscles and the dermis heartkidney and internal organs [17 121 122] Brown adiposewas considered absent in adult humans but recently studieshave shown that Brown adipose tissue may be stimulatedin adults and might have a relevant role in the treatmentof obesity [123] Estrogens promote fat deposition aftersexual maturation and alter the lipid profile However fatalso increases in menopausal women which suggests thatestrogens play an important role in adipocyte differentiationExperimental studies have shown that estrogens can intensifythe thermogenic property of brown adipocytes by an increaseof uncoupling protein 1 (UCP1) mRNA expression [62 124]ER120572 is expressed in BAT tissue and mainly localized inmitochondria which indicated that BATmitochondria couldbe targeted by estrogens and pointed out the possible role


of ER120572 in mitochondriogenesis [125] Tissue estrogen sulfo-transferase (EST) is a critical mediator of estrogen actionEST inhibits estrogen activity by conjugating a sulfonategroup to estrogens thereby preventing biding to estrogenreceptors [126] EST is expressed in adipose tissue andreduces adipocyte size although an overexpression of EST insc and visceral adipose tissue may induce insulin resistanceThe role of EST in development of type 2 DM and metabolicsyndrome is controversial [127 128]

6 Estrogen and Adipokine Secretion

Estrogens may exert effects on several adipokines that areproduced by adipocytes Estrogen levels in premenopausalwomen are closely associated with leptin levels [129 130]Leptin may modulate energy balance in the hypothalamusby exerting an anorectic effect and also it exhibits a lipolyticeffect Estrogen increases leptin sensitivity by controlling theexpression of leptin-specific receptors [130ndash132]

Adiponectin is inversely associated with estrogen levelsThis adipokine is involved in various inflammatory processesendothelial function modulation and protection againstinsulin resistance syndrome Adiponectin plasma level isindirectly and negatively correlated with E2 plasma levelsOophorectomy of adult mice increases adiponectin which isreversed by E2 replacement [133ndash135]

Resistin is a hormone that is produced by adipocytesand contributes to obesity The subcutaneous injection ofestradiol benzoate reduces resistin levels in adipocytes [136]

Evidence from aromatase ArKo deficient models con-tributes to these observations These mice develop a trun-cal obesity phenotype with increased gonadal and visceraladiposity and three times higher levels of circulating leptinwithout a marked increase in body weight [137] Fat cellcan produce proinflammatory adipocytokines that inducemany of the complications of obesity like CD68 TNF120572 orIL6 Administration of estrogens to ovariectomized femalemice reduces significantly the mRNA of IL6 TNF120572 andCD68 Furthermore estrogen prevented female mice fromdeveloping liver steatosis and frombecoming insulin resistant[72 138]

7 Estrogen-Like Compounds andEndocrine Disruptors

Some chemicals and plants derived compounds that mayregulate the activity of estrogen receptors are potential obe-sogens [139] The effect of tibolona a synthetic substancewith estrogenic activity on body weight in postmenopausalwomen has been evaluated [140 141] One-year tibolonatreatment decreases fat mass However tibolona combinedwith 17-120573-estradiol andnorethindrone acetate for 2 years doesnot significantly decrease fat mass [142] The combination ofhormone replacement therapy and tibolona in menopausalwomen increases body mass index (BMI) fat-free mass(FFM) free estrogen index (FEI) and free testosterone index(FTI) but the waist-to-hip ratio (WHR) decreases aftertreatment with tibolona [142] Genistein is phytoestrogen

that has similarity in structure with the human femalehormone 17-120573-estradiol which can bind to both alpha andbeta estrogen receptors and mimic the action of estrogens ontarget organs Genistein is present in soy and it is popularlyused in postmenopausal women Genistein tends to induceobesity at low doses but higher doses increase fatty acidoxidation and reduce fat accumulation in the liver [117 143]However Genistein reverses the truncal fat accumulation inpostmenopausal women and ovariectomized rodent models[144 145]

Obesity is caused by a combination of genetic and envi-ronmental factors [146] Some xenobiotics in the environ-ment impair the normal control of various nuclear receptorsor induce an adipogenic effect The role of these endocrinedisruptors in sexual behavior menopause and some gonadaldiseases has been examined due to their modulation ofestrogen receptor activity Numerous chemicals and plantsderived compounds such as bisphenol A (BPA) phthalatesand heavymetals exhibit estrogenic activity [147ndash150] Manyendocrine disruptors may affect the transcriptional activityof nuclear receptors by changing the action of competitivelybinding with ligand biding domain which may modifycoactivator activity and dissociate corepressors that reducedeacetylases action Some endocrine disruptors may alsomodify DNAmethylation in the regulatory region of specificgenes Furthermore some of themmay activate the phospho-rylation of proteins [151 152]

Endocrine disrupters may also be involved in differentestrogenic intervention processes such as the glycolytic path-way and during the regulation of glucose transporters withcompounds like BPA 4-nonylphenol (NP) 4-octylphenol(OP) and 4-propylphenol [116 153 154] Endocrine disrup-tion using these substances also interferes with tricarboxylicacidmetabolismby decreasing key enzymes inmitochondrialactivity which could be partially related to obesity (Figure 4)

In addition to these findings many other estrogen-mediated pathways may be modulated by endocrine disrup-tors Further studies are required to clarify the involvementof these chemicals

8 Estrogen Therapy and Obesity

A growing body of evidence now demonstrates that estro-genic signaling can have an important role in obesity devel-opment inmenopausalwomenMenopausalwomen are threetimesmore likely to develop obesity andmetabolic syndromeabnormalities than premenopausal women [155] Further-more estrogenprogestin based hormone replacement ther-apy in menopausal women has been shown to lower visceraladipose tissue fasting serum glucose and insulin levels [70156] Estrogens also reduce the cardiovascular risk factorsthat increase during menopause Therefore estrogen therapymay exert a positive impact by reducing total cholesterol andrelative LDL levels [157]

The estrogen type and route of administration appearsto affect clinical outcomes The changes in body fat dis-tribution during menopause have led some researchersto suggest that hormone replacement therapy beneficially


OH

HH

HO

H

ClClCl

C

CH

ClCl

OHHO

HO O

OOHOH

Genistein

Bisphenol A

DDT

EstradiolEndogenous

estrogen

Pesticide

Plasticscomponent

Phytoestrogen

Figure 4 Components with estrogens effects Estrogen and someendocrine disruptors that have an estrogenic effect DDT is a chem-ical fertilizer Bisphenol A is an organic compound used to makepolycarbonate polymers and epoxy resins Genistein is an isofla-vone found in a number of plants including soy DDT dichlorodi-phenyltrichloroethane

affects obesity in this group To evaluate the metaboliceffects of hormone replacement therapy using transdermalpatches of 17-120573-estradiol with medroxyprogesterone acetatein obese and nonobese menopausal women demonstratedgreater fat loss [158] Recent study participants in themost current WHI report were assigned to single estrogentherapy (0625mgday conjugated equine estrogens) andcombined estrogenprogestin therapy (0625mg conjugatedequine estrogens plus 25mg medroxyprogesterone acetate)An assessment of body composition using dual energy X-ray (DXA) absorptiometry at the six-year follow-up demon-strated a decrease in the loss of body fat mass with hormonaltherapy in the first three years but not after six years [159ndash161] However the physiological form of estrogen is E2 andit is available in some oral preparations as well as all patchescreams and gels for transdermal or percutaneous absorptionIn contrast to orally administered HRT transdermal deliveryavoid first pass liver metabolism thereby resulting in morestable serum levels without supraphysiological liver exposure[162]

A meta-analysis of over 100 randomized trials inmenopausal women has analyzed the effect of HRT oncomponents of metabolic syndrome The authors concludethat in women without diabetes both oral and transdermalestrogen with or without progestin increase lean body massreduce abdominal fat improve insulin resistance decrease

LDLhigh-density-lipoprotein cholesterol ratio and decreaseblood pressure [163]

9 Conclusion

Hormone therapy during menopause will always be a mixedpicture of benefits and risks The data suggest that formenopausal women of age 50 to 59 y or younger than age60 y the benefits of menopause hormone therapy outweighthe risks in many instances and particularly for relief ofsymptoms due to estrogen deficiency Judgments abouttreatment require assessment of the needs in an individualpatient and her potential for risk such as breast cancercoronary heart disease fracture stroke obesity and deepvenous thrombosis In order to reduce the obesity pandemicwe consider that usingmenopause hormonal therapywith thelowest effective dose and for the shortest duration may be apossible coadjutant therapy Future research should focus onidentifying critical brain sites where ERs regulate bodyweighthomeostasis and delineate the intracellular signal pathwaysthat are required for the actions of estrogens Moreoverunderstanding the genetics and epigenetics role of moleculesthat may play a role in estrogen activity in adipose tissue mayreveal new pharmacological target for the beneficial actionof estrogens However stringent studies in different locationsaround theworld are essential to determine the real beneficialeffect of estrogens for obesity treatment during menopause

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] M A Mendez C A Monteiro and B M Popkin ldquoOverweightexceeds underweight among women in most developing coun-triesrdquo American Journal of Clinical Nutrition vol 81 no 3 pp714ndash721 2005

[3] K M Olszowy D L Dufour R L Bender T A Bekelmanand J C Reina ldquoSocioeconomic status stature and obesity inwomen 20-year trends in urban Colombiardquo American Journalof Human Biology vol 24 pp 602ndash610 2012

[4] Y Seki L Williams P M Vuguin and M J Charron ldquoMinire-view epigenetic programming of diabetes and obesity animalmodelsrdquo Endocrinology vol 153 no 3 pp 1031ndash1038 2012

[5] B L Heitmann K R Westerterp R J Loos et al ldquoObesitylessons from evolution and the environmentrdquo Obesity Reviewsvol 13 pp 910ndash922 2012

[6] S Hagan and K D Niswender ldquoNeuroendocrine regulation offood intakerdquo Pediatric Blood and Cancer vol 58 no 1 pp 149ndash153 2012

[7] M Myslobodsky ldquoMolecular network of obesity what does itpromise for pharmacotherapyrdquo Obesity Reviews vol 9 no 3pp 236ndash245 2008


[8] K A Simpson N M Martin and S R Bloom ldquoHypothalamicregulation of food intake and clinical therapeutic applicationsrdquoArquivos Brasileiros de Endocrinologia eMetabologia vol 53 no2 pp 120ndash128 2009

[9] G D Lopaschuk J R Ussher and J S Jaswal ldquoTargetingintermediary metabolism in the hypothalamus as a mechanismto regulate appetiterdquo Pharmacological Reviews vol 62 no 2 pp237ndash264 2010

[10] M M Musri and M Parrizas ldquoEpigenetic regulation of adi-pogenesisrdquo Current Opinion in Clinical Nutrition amp MetabolicCare vol 15 pp 342ndash349 2012

[11] S Sookoian and C J Pirola ldquoDNA methylation and hepaticinsulin resistance and steatosisrdquo Current Opinion in ClinicalNutrition amp Metabolic Care vol 15 pp 350ndash356 2012

[12] Y Nie R C Ma J C Chan H Xu and G Xu ldquoGlucose-dependent insulinotropic peptide impairs insulin signalingvia inducing adipocyte inflammation in glucose-dependentinsulinotropic peptide receptor-overexpressing adipocytesrdquoFASEB Journal vol 26 pp 2383ndash2393 2012

[13] S L Schmidt K AHarmon T A Sharp EH Kealey andDHBessesen ldquoThe effects of overfeeding on spontaneous physicalactivity in obesity prone and obesity resistant humansrdquoObesityvol 20 pp 2183ndash2193 2012

[14] F Magkos E Fabbrini C Conte B W Patterson and SKlein ldquoRelationship between adipose tissue lipolytic activityand skeletal muscle insulin resistance in nondiabetic womenrdquoJournal of Clinical Endocrinology and Metabolism vol 97 ppE1219ndashE1223 2012

[15] P Bjorntorp ldquoThe associations between obesity adipose tissuedistribution and diseaserdquo Acta Medica Scandinavica vol 223no 723 pp 121ndash134 1988

[16] C S Fox C C White K Lohman et al ldquoGenome-wideassociation of pericardial fat identifies a unique locus for ectopicfatrdquo PLOS Genetics vol 8 Article ID e1002705 2012

[17] F Lizcano and D Vargas ldquoEID1-induces brown-like adipocytetraits in white 3T3-L1 pre-adipocytesrdquoBiochemical and Biophys-ical Research Communications vol 398 no 2 pp 160ndash165 2010

[18] D L Morganstein P Wu M R Mane N M Fisk R Whiteand M G Parker ldquoHuman fetal mesenchymal stem cellsdifferentiate into brown and white adipocytes a role for ERR120572in human UCP1 expressionrdquo Cell Research vol 20 no 4 pp434ndash444 2010

[19] AM Cypess andC R Kahn ldquoBrown fat as a therapy for obesityand diabetesrdquo Current Opinion in Endocrinology Diabetes andObesity vol 17 no 2 pp 143ndash149 2010

[20] Y-H Tseng E Kokkotou T J Schulz et al ldquoNew role of bonemorphogenetic protein 7 in brown adipogenesis and energyexpenditurerdquo Nature vol 454 no 7207 pp 1000ndash1004 2008

[21] A G Cristancho and M A Lazar ldquoForming functional fata growing understanding of adipocyte differentiationrdquo NatureReviews Molecular Cell Biology vol 12 no 11 pp 722ndash734 2011

[22] NMaenhaut and J van de Voorde ldquoRegulation of vascular toneby adipocytesrdquo BMCMedicine vol 9 article 25 2011

[23] H J Harwood Jr ldquoThe adipocyte as an endocrine organ in theregulation of metabolic homeostasisrdquo Neuropharmacology vol63 pp 57ndash75 2012

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[25] V Wietlisbach P Marques-Vidal K Kuulasmaa J Karvanenand F Paccaud ldquoThe relation of body mass index and abdom-inal adiposity with dyslipidemia in 27 general populationsof the WHO MONICA Projectrdquo Nutrition Metabolism andCardiovascular Diseases vol 2 no 5 pp 432ndash442 2013

[26] K M Flegal M D Carroll C L Ogden and L R CurtinldquoPrevalence and trends in obesity amongUS adults 1999ndash2008rdquoJournal of the American Medical Association vol 303 no 3 pp235ndash241 2010

[27] Y Wu ldquoOverweight and obesity in Chinardquo British MedicalJournal vol 333 no 7564 pp 362ndash363 2006

[28] A Ramachandran and C Snehalatha ldquoRising burden of obesityin Asiardquo Journal of Obesity vol 2010 Article ID 868573 8 pages2010

[29] W T Garvey D H Ryan M Look et al ldquoTwo-year sus-tained weight loss and metabolic benefits with controlled-release phenterminetopiramate in obese and overweight adults(SEQUEL) a randomized placebo-controlled phase 3 exten-sion studyrdquo American Journal of Clinical Nutrition vol 95 no2 pp 297ndash308 2012

[30] D J Clegg ldquoMinireview the year in review of estrogenregulation ofmetabolismrdquoMolecular Endocrinology vol 26 pp1957ndash1960 2012

[31] M C Carr ldquoThe emergence of the metabolic syndrome withmenopauserdquo Journal of Clinical Endocrinology and Metabolismvol 88 no 6 pp 2404ndash2411 2003

[32] FMauvais-Jarvis ldquoEstrogen and androgen receptors regulatorsof fuel homeostasis and emerging targets for diabetes andobesityrdquo Trends in Endocrinology and Metabolism vol 22 no1 pp 24ndash33 2011

[33] P H Casey R H Bradley L Whiteside-Mansell K Barrett JM Gossett and P M Simpson ldquoEvolution of obesity in a lowbirth weight cohortrdquo Journal of Perinatology vol 32 no 2 pp91ndash96 2012

[34] S R Davis C Castelo-Branco P Chedraui et al ldquoUnderstand-ing weight gain at menopauserdquoClimacteric vol 15 pp 419ndash4292012

[35] A Liberati D G Altman J Tetzlaff et al ldquoThe PRISMAstatement for reporting systematic reviews and meta-analysesof studies that evaluate health care interventions explanationand elaborationrdquo J Clin Epidemiol vol 62 pp e1ndash34 2009

[36] P A Heine J A Taylor G A Iwamoto D B Lubahn andP S Cooke ldquoIncreased adipose tissue in male and femaleestrogen receptor-120572 knockoutmicerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 97 no23 pp 12729ndash12734 2000

[37] Y Murata K M Robertson M E E Jones and E R SimpsonldquoEffect of estrogen deficiency in the male the ArKO mousemodelrdquo Molecular and Cellular Endocrinology vol 193 no 1-2pp 7ndash12 2002

[38] F Grodstein J E Manson G A Colditz W C Willett F ESpeizer and M J Stampfer ldquoA prospective observational studyof postmenopausal hormone therapy and primary preventionof cardiovascular diseaserdquo Annals of Internal Medicine vol 133no 12 pp 933ndash941 2000

[39] C Bouchard J-P Despres and P Mauriege ldquoGenetic andnongenetic determinants of regional fat distributionrdquoEndocrineReviews vol 14 no 1 pp 72ndash93 1993

[40] M Garaulet F Perez-Llamas J C Baraza et al ldquoBody fatdistribution in pre- and post-menopausal women metabolicand anthropometric variablesrdquo Journal of Nutrition Health andAging vol 6 no 2 pp 123ndash126 2002


[41] M Garaulet F Perez-Llamas S Zamora and F Javier TebarldquoComparative study of the type of obesity in pre- and post-menopausal women relationship with fat cell data fatty acidcomposition and endocrine metabolic nutritional and psycho-logical variablesrdquo Medicina Clinica vol 118 no 8 pp 281ndash2862002

[42] M J Toth E T Poehlman D E Matthews A Tchernof andM J MacCoss ldquoEffects of estradiol and progesterone on bodycomposition protein synthesis and lipoprotein lipase in ratsrdquoAmerican Journal of Physiology vol 280 no 3 pp E496ndashE5012001

[43] J M H Elbers S De Jong T Teerlink H Asscheman J CSeidell and L J G Gooren ldquoChanges in fat cell size and invitro lipolytic activity of abdominal and gluteal adipocytes aftera one-year cross-sex hormone administration in transsexualsrdquoMetabolism vol 48 no 11 pp 1371ndash1377 1999

[44] J M H Elbers H Asscheman J C Seidell and L J GGooren ldquoEffects of sex steroid hormones on regional fat depotsas assessed by magnetic resonance imaging in transsexualsrdquoAmerican Journal of Physiology vol 276 no 2 pp E317ndashE3251999

[45] L R Nelson and S E Bulun ldquoEstrogen production and actionrdquoJournal of the American Academy of Dermatology vol 45 no 3pp S116ndashS124 2001

[46] Z Shen T Saloniemi A Ronnblad P Jarvensivu P Pakarinenand M Poutanen ldquoSex steroid-dependent and -independentaction of hydroxysteroid (17120573) dehydrogenase 2 evidence fromtransgenic female micerdquo Endocrinology vol 150 no 11 pp4941ndash4949 2009

[47] Z Weihua S Andersson G Cheng E R Simpson M Warnerand J-A Gustafsson ldquoUpdate on estrogen signalingrdquo FEBSLetters vol 546 no 1 pp 17ndash24 2003

[48] S Banerjee K L Chambliss CMineo and PW Shaul ldquoRecentinsights into non-nuclear actions of estrogen receptor alphardquoSteroids 2013

[49] S S Simons Jr D P Edwards and R Kumar ldquoDynamic struc-tures of nuclear hormone receptors new promises and chal-lengesrdquo Molecular Endocrinology vol 28 no 2 pp 173ndash1822013

[50] R P A Barros and J-A Gustafsson ldquoEstrogen receptors and themetabolic networkrdquo Cell Metabolism vol 14 no 3 pp 289ndash2992011

[51] M H Faulds C Zhao K Dahlman-Wright and J-AGustafsson ldquoThe diversity of sex steroid action regulation ofmetabolism by estrogen signalingrdquo Journal of Endocrinologyvol 212 no 1 pp 3ndash12 2012

[52] S Safe and K Kim ldquoNon-classical genomic estrogen receptor(ER)specificity protein and ERactivating protein-1 signalingpathwaysrdquo Journal of Molecular Endocrinology vol 41 no 5-6pp 263ndash275 2008

[53] M Almeida L Han C A OrsquoBrien S Kousteni and SC Manolagas ldquoClassical genotropic versus kinase-initiatedregulation of gene transcription by the estrogen receptor 120572rdquoEndocrinology vol 147 no 4 pp 1986ndash1996 2006

[54] S Kousteni T Bellido L I Plotkin et al ldquoNongenotropicsex-nonspecific signaling through the estrogen or androgenreceptors dissociation from transcriptional activityrdquo Cell vol104 no 5 pp 719ndash730 2001

[55] E R Levin ldquoCellular functions of the plasma membraneestrogen receptorrdquo Trends in Endocrinology and Metabolismvol 10 no 9 pp 374ndash376 1999

[56] A J Evinger III and E R Levin ldquoRequirements for estrogenreceptor 120572 membrane localization and functionrdquo Steroids vol70 no 5ndash7 pp 361ndash363 2005

[57] T Oosthuyse and A N Bosch ldquoOestrogenrsquos regulation of fatmetabolismduring exercise and gender specific effectsrdquoCurrentOpinion in Pharmacology vol 12 pp 363ndash371 2012

[58] F Mauvais-Jarvis D J Clegg and A L Hevener ldquoThe role ofestrogens in control of energy balance and glucose homeosta-sisrdquo Endocrine Reviews vol 34 pp 309ndash338 2013

[59] W L Miller and R J Auchus ldquoThe molecular biology bio-chemistry and physiology of human steroidogenesis and itsdisordersrdquo Endocrine Reviews vol 32 no 1 pp 81ndash151 2011

[60] C Weigt T Hertrampf N Zoth K H Fritzemeier and P DielldquoImpact of estradiol ER subtype specific agonists and genisteinon energy homeostasis in a rat model of nutrition inducedobesityrdquo Molecular and Cellular Endocrinology vol 351 no 2pp 227ndash238 2012

[61] S Rodrıguez-Cuenca M Monjo M Gianotti A M Proenzaand P Roca ldquoExpression of mitochondrial biogenesis-signalingfactors in brown adipocytes is influenced specifically by 17120573-estradiol testosterone and progesteronerdquo American Journal ofPhysiology vol 292 no 1 pp E340ndashE346 2007

[62] S Rodriguez-Cuenca M Monjo M Frontera M Gianotti AM Proenza andP Roca ldquoSex steroid receptor expression profilein brown adipose tissue Effects of hormonal statusrdquo CellularPhysiology and Biochemistry vol 20 no 6 pp 877ndash886 2007

[63] C J Park Z Zhao C Glidewell-Kenney et al ldquoGenetic rescueof nonclassical ER120572 signaling normalizes energy balance inobese Er120572-null mutant micerdquo Journal of Clinical Investigationvol 121 no 2 pp 604ndash612 2011

[64] R Kumar and I J McEwan ldquoAllosteric modulators of steroidhormone receptors structural dynamics and gene regulationrdquoEndocrine Reviews vol 33 pp 271ndash299 2012

[65] X Lu L PengM Lv andK ding ldquoRecent advance in the designof small molecular modulators of estrogen-related receptorsrdquoCurrent Pharmaceutical Design vol 18 pp 3421ndash3431 2012

[66] K Casazza G P Page and J R Fernandez ldquoThe associationbetween the rs2234693 and rs9340799 estrogen receptor 120572 genepolymorphisms and risk factors for cardiovascular disease areviewrdquo Biological Research for Nursing vol 12 no 1 pp 84ndash972010

[67] R Pastorelli D Carpi L Airoldi et al ldquoProteome analysisfor the identification of in vivo estrogen-regulated proteins inbonerdquo Proteomics vol 5 no 18 pp 4936ndash4945 2005

[68] J C Lovejoy ldquoThe menopause and obesityrdquo Primary Care vol30 no 2 pp 317ndash325 2003

[69] S B Pedersen K Kristensen P A Hermann J A Katzenel-lenbogen and B Richelsen ldquoEstrogen controls lipolysis by up-regulating 1205722A-adrenergic receptors directly in human adiposetissue through the estrogen receptor 120572 Implications for thefemale fat distributionrdquo Journal of Clinical Endocrinology andMetabolism vol 89 no 4 pp 1869ndash1878 2004

[70] L C Gormsen C Host B E Hjerrild et al ldquoEstradiol acutelyinhibits whole body lipid oxidation and attenuates lipoly-sis in subcutaneous adipose tissue a randomized placebo-controlled study in postmenopausal womenrdquo European Journalof Endocrinology vol 167 pp 543ndash551 2012

[71] H Zang M Ryden K Wahlen K Dahlman-Wright P ArnerandA LHirschberg ldquoEffects of testosterone and estrogen treat-ment on lipolysis signaling pathways in subcutaneous adiposetissue of postmenopausal womenrdquo Fertility and Sterility vol 88no 1 pp 100ndash106 2007


[72] R Yonezawa T Wada N Matsumoto et al ldquoCentral ver-sus peripheral impact of estradiol on the impaired glucosemetabolism in ovariectomized mice on a high-fat dietrdquo Ameri-can Journal of Physiology vol 303 pp E445ndashE456 2012

[73] K M Gavin E E Cooper D K Raymer and R C HicknerldquoEstradiol effects on subcutaneous adipose tissue lipolysis inpremenopausal women are adipose tissue depot specific andtreatment dependentrdquo American Journal of Physiology vol 304pp E1167ndashE1174 2013

[74] M Monjo E Pujol and P Roca ldquo1205722- to 1205733-adrenoceptorswitch in 3T3-L1 preadipocytes and adipocytes modulationby testosterone 17120573-estradiol and progesteronerdquo AmericanJournal of Physiology vol 289 no 1 pp E145ndashE150 2005

[75] S Tessier E Riesco M Lacaille et al ldquoImpact of walking onadipose tissue lipoprotein lipase activity and expression in pre-and postmenopausal womenrdquo Obesity Facts vol 3 no 3 pp191ndash199 2010

[76] S Jeong and M Yoon ldquo17120573-Estradiol inhibition of PPAR120574-induced adipogenesis and adipocyte-specific gene expressionrdquoActa Pharmacologica Sinica vol 32 no 2 pp 230ndash238 2011

[77] E D G Abeles L M D S Cordeiro A D S Martins etal ldquoEstrogen therapy attenuates adiposity markers in sponta-neously hypertensive ratsrdquo Metabolism vol 61 pp 1100ndash11072012

[78] T Beckett A Tchernof and M J Toth ldquoEffect of ovariectomyand estradiol replacement on skeletal muscle enzyme activity infemale ratsrdquoMetabolism vol 51 no 11 pp 1397ndash1401 2002

[79] C Stirone A Boroujerdi S P Duckles and D N KrauseldquoEstrogen receptor activation of phosphoinositide-3 kinaseAkt and nitric oxide signaling in cerebral blood vessels rapidand long-term effectsrdquo Molecular Pharmacology vol 67 no 1pp 105ndash113 2005

[80] E Bossy-Wetzel and D R Green ldquoApoptosis checkpoint at themitochondrial frontierrdquo Mutation Research vol 434 no 3 pp243ndash251 1999

[81] N H Rogers C A Witczak M F Hirshman L J Goodyearand A S Greenberg ldquoEstradiol stimulates Akt AMP-activatedprotein kinase (AMPK) and TBC1D14 but not glucose uptakein rat soleusrdquo Biochemical and Biophysical Research Communi-cations vol 382 no 4 pp 646ndash650 2009

[82] W A Alaynick ldquoNuclear receptors mitochondria and lipidmetabolismrdquoMitochondrion vol 8 no 4 pp 329ndash337 2008

[83] S P Kalra M G Dube S Pu B Xu T L Horvath andP S Kalra ldquoInteracting appetite-regulating pathways in thehypothalamic regulation of body weightrdquo Endocrine Reviewsvol 20 no 1 pp 68ndash100 1999

[84] A Kostanyan and K Nazaryan ldquoRat brain glycolysis regulationby estradiol-17120573rdquo Biochimica et Biophysica Acta vol 1133 no 3pp 301ndash306 1992

[85] K W Kim J-W Sohn D Kohno Y Xu K Williams andJ K Elmquist ldquoSF-1 in the ventral medial hypothalamicnucleus a key regulator of homeostasisrdquoMolecular and CellularEndocrinology vol 336 no 1-2 pp 219ndash223 2011

[86] I S Farooqi and S OrsquoRahilly ldquoGenetics of obesity in humansrdquoEndocrine Reviews vol 27 no 7 pp 710ndash718 2006

[87] P C Butera ldquoEstradiol and the control of food intakerdquo Physiol-ogy and Behavior vol 99 no 2 pp 175ndash180 2010

[88] Y Xu T P Nedungadi L Zhu et al ldquoDistinct hypothalamicneurons mediate estrogenic effects on energy homeostasis andreproductionrdquo Cell Metabolism vol 14 no 4 pp 453ndash465 2011

[89] S Obici ldquoMinireview molecular targets for obesity therapy inthe brainrdquo Endocrinology vol 150 no 6 pp 2512ndash2517 2009

[90] S Hart-Unger and K S Korach ldquoEstrogens and obesity is it allin our headsrdquo Cell Metabolism vol 14 no 4 pp 435ndash436 2011

[91] T A Roepke ldquoOestrogen modulates hypothalamic control ofenergy homeostasis through multiple mechanismsrdquo Journal ofNeuroendocrinology vol 21 no 2 pp 141ndash150 2009

[92] R Slamberova O C Hnatczuk and I Vathy ldquoExpression ofproopiomelanocortin and proenkephalin mRNA in sexuallydimorphic brain regions are altered in adult male and femalerats treated prenatally with morphinerdquo Journal of PeptideResearch vol 63 no 5 pp 399ndash408 2004

[93] J W Hill J H Urban M Xu and J E Levine ldquoEstrogeninduces neuropeptide Y (NPY) Y1 receptor gene expression andresponsiveness to NPY in gonadotrope-enriched pituitary cellculturesrdquo Endocrinology vol 145 no 5 pp 2283ndash2290 2004

[94] F S J de Souza S Nasif R Lopez-Leal D H Levi M J Lowand M Rubinsten ldquoThe estrogen receptor 120572 colocalizes withproopiomelanocortin in hypothalamic neurons and binds to aconservedmotif present in the neuron-specific enhancer nPE2rdquoEuropean Journal of Pharmacology vol 660 no 1 pp 181ndash1872011

[95] M Kojima H Hosoda Y Date M Nakazato H Matsuo andK Kangawa ldquoGhrelin is a growth-hormone-releasing acylatedpeptide from stomachrdquoNature vol 402 no 6762 pp 656ndash6601999

[96] M Kojima and K Kangawa ldquoGhrelin structure and functionrdquoPhysiological Reviews vol 85 no 2 pp 495ndash522 2005

[97] M Nakazato N Murakami Y Date et al ldquoA role for ghrelin inthe central regulation of feedingrdquo Nature vol 409 no 6817 pp194ndash198 2001

[98] K Dafopoulos N Chalvatzas G Kosmas A Kallitsaris SPournaras and I EMessinis ldquoThe effect of estrogens on plasmaghrelin concentrations in womenrdquo Journal of EndocrinologicalInvestigation vol 33 no 2 pp 109ndash112 2010

[99] B Pillot C Duraffourd M Begeot et al ldquoRole of hypothalamicmelanocortin system in adaptation of food intake to foodprotein increase in micerdquo PLoS ONE vol 6 no 4 Article IDe19107 2011

[100] M J Krashes S Koda C Ye et al ldquoRapid reversible activationof AgRP neurons drives feeding behavior in micerdquo Journal ofClinical Investigation vol 121 no 4 pp 1424ndash1428 2011

[101] H Biebermann P Kuhnen G Kleinau and H Krude ldquoTheneuroendocrine circuitry controlled by POMC MSH andAGRPrdquo Handbook of Experimental Pharmacology vol 209 pp47ndash75 2012

[102] M M Messina G Boersma J M Overton and L AEckel ldquoEstradiol decreases the orexigenic effect of melanin-concentrating hormone in ovariectomized ratsrdquo Physiology andBehavior vol 88 no 4-5 pp 523ndash528 2006

[103] J Santollo and L A Eckel ldquoThe orexigenic effect of melanin-concentrating hormone (MCH) is influenced by sex and stageof the estrous cyclerdquo Physiology and Behavior vol 93 no 4-5pp 842ndash850 2008

[104] T L Horvath ldquoSynaptic plasticity in energy balance regulationrdquoObesity vol 14 supplement 5 pp 228Sndash233S 2006

[105] J-L Nahon ldquoThe melanocortins and melanin-concentratinghormone in the central regulation of feeding behavior andenergy homeostasisrdquo Comptes Rendus Biologies vol 329 no 8pp 623ndash638 2006


[106] E Riant A Waget H Cogo J-F Arnal R Burcelin andP Gourdy ldquoEstrogens protect against high-fat diet-inducedinsulin resistance and glucose intolerance in micerdquo Endocrinol-ogy vol 150 no 5 pp 2109ndash2117 2009

[107] R P A Barros C Gabbi A Morani M Warner and J-AGustafsson ldquoParticipation of ER120572 and ER120573 in glucose home-ostasis in skeletal muscle and white adipose tissuerdquo AmericanJournal of Physiology vol 297 no 1 pp E124ndashE133 2009

[108] A Naaz M Zakroczymski P Heine et al ldquoEffect of ovariec-tomy on adipose tissue of mice in the absence of estrogenreceptor alpha (ER120572) a potential role for estrogen receptor beta(ER120573)rdquo Hormone and Metabolic Research vol 34 no 11-12 pp758ndash763 2002

[109] B L Wajchenberg ldquoSubcutaneous and visceral adipose tissuetheir relation to the metabolic syndromerdquo Endocrine Reviewsvol 21 no 6 pp 697ndash738 2000

[110] PAntonson YOmoto PHumire and J AGustafsson ldquoGener-ation of ERalpha-floxed and knockoutmice using the CreLoxPsystemrdquoBiochemical and Biophysical Research Communicationsvol 424 pp 710ndash716 2012

[111] N Geary L Asarian K S Korach D W Pfaff and S OgawaldquoDeficits in E2-dependent control of feeding weight gain andcholecystokinin satiation in ER-120572nullmicerdquoEndocrinology vol142 no 11 pp 4751ndash4757 2001

[112] Q Gao G Mezei Y Nie et al ldquoAnorectic estrogen mimicsleptinrsquos effect on the rewiring of melanocortin cells and Stat3signaling in obese animalsrdquo Nature Medicine vol 13 no 1 pp89ndash94 2007

[113] L Yan H Ge H Li et al ldquoGender-specific proteomic alter-ations in glycolytic and mitochondrial pathways in agingmonkey heartsrdquo Journal of Molecular and Cellular Cardiologyvol 37 no 5 pp 921ndash929 2004

[114] C M Cheng M Cohen J I E Wang and C A BondyldquoEstrogen augments glucose transporter and IGF1 expression inprimate cerebral cortexrdquo FASEB Journal vol 15 no 6 pp 907ndash915 2001

[115] C Stirone S P Duckles D N Krause and V Procaccio ldquoEstro-gen increases mitochondrial efficiency and reduces oxidativestress in cerebral blood vesselsrdquo Molecular Pharmacology vol68 no 4 pp 959ndash965 2005

[116] A Razmara L Sunday C Stirone et al ldquoMitochondrial effectsof estrogen are mediated by estrogen receptor 120572 in brainendothelial cellsrdquo Journal of Pharmacology and ExperimentalTherapeutics vol 325 no 3 pp 782ndash790 2008

[117] R N Singh Yadav ldquoIsocitrate dehydrogenase activity and itsregulation by estradiol in tissues of rats of various agesrdquo CellBiochemistry and Function vol 6 no 3 pp 197ndash202 1988

[118] E Amengual-Cladera I LladoM Gianotti andAM ProenzaldquoRetroperitoneal white adipose tissue mitochondrial functionand adiponectin expression in response to ovariectomy and17120573-estradiol replacementrdquo Steroids vol 77 no 6 pp 659ndash6652012

[119] H Homma H Kurachi Y Nishio et al ldquoEstrogen suppressestranscription of lipoprotein lipase gene Existence of a uniqueestrogen response element on the lipoprotein lipase promoterrdquoJournal of Biological Chemistry vol 275 no 15 pp 11404ndash114112000

[120] R Leclere R Torregrosa-Munumer R Kireev et al ldquoEffect ofestrogens on base excision repair in brain and liver mitochon-dria of aged female ratsrdquo Biogerontology vol 14 pp 383ndash3942013

[121] C S TamV Lecoultre E Ravussin et al ldquoBrown adipose tissuemechanisms and potential therapeutic targetsrdquo Circulation vol125 pp 2782ndash2791 2012

[122] D M Nikolic Y Li S Liu and S Wang ldquoOverexpression ofconstitutively active PKG-I protects female but not male micefrom diet-induced obesityrdquo Obesity vol 19 no 4 pp 784ndash7912011

[123] M Matsushita T Yoneshiro S Aita T Kameya H Sugie andM Saito ldquoImpact of brown adipose tissue on body fatness andglucose metabolism in healthy humansrdquo International Journalof Obesity 2013

[124] S B Pedersen J M Bruun K Kristensen and B RichelsenldquoRegulation of UCP1 UCP2 and UCP3 mRNA expression inbrown adipose tissue white adipose tissue and skeletal musclein rats by estrogenrdquo Biochemical and Biophysical ResearchCommunications vol 288 no 1 pp 191ndash197 2001

[125] K Velickovic A Cvoro B Srdic et al ldquoExpression and subcel-lular localization of estrogen receptors alpha and beta in humanfetal brown adipose tissuerdquo Journal of Clinical Endocrinologyand Metabolism 2013

[126] C A Strott ldquoSteroid sulfotransferasesrdquo Endocrine Reviews vol17 no 6 pp 670ndash697 1996

[127] TWada C A Ihunnah J Gao et al ldquoEstrogen sulfotransferaseinhibits adipocyte differentiationrdquo Molecular Endocrinologyvol 25 no 9 pp 1612ndash1623 2011

[128] F Mauvais-Jarvis ldquoEstrogen sulfotransferase intracrinologymeets metabolic diseasesrdquoDiabetes vol 61 pp 1353ndash1354 2012

[129] N A Tritos G Segal-Lieberman P S Vezeridis and EMaratos-Flier ldquoEstradiol-induced anorexia is independent ofleptin and melanin-concentrating hormonerdquo Obesity Researchvol 12 no 4 pp 716ndash724 2004

[130] S R Ladyman and D R Grattan ldquoSuppression of leptinreceptor mRNA and leptin responsiveness in the ventromedialnucleus of the hypothalamus during pregnancy in the ratrdquoEndocrinology vol 146 no 9 pp 3868ndash3874 2005

[131] D J Clegg L M Brown S C Woods and S C BenoitldquoGonadal hormones determine sensitivity to central leptin andinsulinrdquo Diabetes vol 55 pp 978ndash987 2006

[132] R A Lobo ldquoMetabolic syndrome after menopause and the roleof hormonesrdquoMaturitas vol 60 no 1 pp 10ndash18 2008

[133] T P Combs U B Pajvani A H Berg et al ldquoA transgenicmousewith a deletion in the collagenous domain of adiponectindisplays elevated circulating adiponectin and improved insulinsensitivityrdquo Endocrinology vol 145 no 1 pp 367ndash383 2004

[134] T P Combs A H Berg M W Rajala et al ldquoSexual differ-entiation pregnancy calorie restriction and aging affect theadipocyte-specific secretory protein adiponectinrdquoDiabetes vol52 no 2 pp 268ndash276 2003

[135] D P Rose D Komninou and G D Stephenson ldquoObesityadipocytokines and insulin resistance in breast cancerrdquoObesityReviews vol 5 no 3 pp 153ndash165 2004

[136] C M Steppan S T Bailey S Bhat et al ldquoThe hormone resistinlinks obesity to diabetesrdquoNature vol 409 no 6818 pp 307ndash3122001

[137] E R Simpson M Misso K N Hewitt et al ldquoEstrogenmdashthegood the bad and the unexpectedrdquo Endocrine Reviews vol 26no 3 pp 322ndash330 2005

[138] R E Stubbins K Najjar V B Holcomb J Hong and N PNunez ldquoOestrogen alters adipocyte biology and protects femalemice from adipocyte inflammation and insulin resistancerdquoDiabetes Obesity andMetabolism vol 14 no 1 pp 58ndash66 2012


[139] F Grun and B Blumberg ldquoMinireview the case for obesogensrdquoMolecular Endocrinology vol 23 no 8 pp 1127ndash1134 2009

[140] A Cagnacci A Renzi M Cannoletta D Pirillo S Aranginoand A Volpe ldquoTibolone and estradiol plus norethisteroneacetate similarly influence endothelium-dependent vasodilata-tion in healthy postmenopausal womenrdquo Fertility and Sterilityvol 86 no 2 pp 480ndash483 2006

[141] I B Meeuwsen M M Samson S A Duursma and H JVerhaar ldquoThe effect of tibolone on fat mass fat-free mass andtotal body water in postmenopausal womenrdquo Endocrinologyvol 142 no 11 pp 4813ndash4817 2001

[142] M A Boyanov and A D Shinkov ldquoEffects of tibolone on bodycomposition in postmenopausal women a 1-year follow upstudyrdquoMaturitas vol 51 no 4 pp 363ndash369 2005

[143] Y M Lee J S Choi M H Kim M H Jung Y S Leeand J Song ldquoEffects of dietary genistein on hepatic lipidmetabolism and mitochondrial function in mice fed high-fatdietsrdquo Nutrition vol 22 no 9 pp 956ndash964 2006

[144] J Wu J Oka I Tabata et al ldquoEffects of isoflavone and exerciseon BMD and fat mass in postmenopausal Japanese women a 1-year randomized placebo-controlled trialrdquo Journal of Bone andMineral Research vol 21 no 5 pp 780ndash789 2006

[145] H-K Kim C Nelson-Dooley M A Della-Fera et al ldquoGenis-tein decreases food intake body weight and fat pad weight andcauses adipose tissue apoptosis in ovariectomized female micerdquoJournal of Nutrition vol 136 no 2 pp 409ndash414 2006

[146] C M Damcott P Sack and A R Shuldiner ldquoThe geneticsof obesityrdquo Endocrinology and Metabolism Clinics of NorthAmerica vol 32 no 4 pp 761ndash786 2003

[147] J G Teeguarden A M Calafat X Ye et al ldquoTwenty-four hourhuman urine and serum profiles of bisphenol A during high-dietary exposurerdquo Toxicological Sciences vol 123 no 1 pp 48ndash57 2011

[148] J J Heindel ldquoRole of exposure to environmental chemicals inthe developmental basis of disease and dysfunctionrdquo Reproduc-tive Toxicology vol 23 no 3 pp 257ndash259 2007

[149] I Bogacka D S Roane X Xi et al ldquoExpression levels of geneslikely involved in glucose-sensing in the obese Zucker rat brainrdquoNutritional Neuroscience vol 7 no 2 pp 67ndash74 2004

[150] G Rasier A-S Parent A Gerard M-C Lebrethon and J-P Bourguignon ldquoEarly maturation of gonadotropin-releasinghormone secretion and sexual precocity after exposure of infantfemale rats to estradiol or dichlorodiphenyltrichloroethanerdquoBiology of Reproduction vol 77 no 4 pp 734ndash742 2007

[151] E Diamanti-Kandarakis J-P Bourguignon L C Giudice etal ldquoEndocrine-disrupting chemicals an endocrine societyscientific statementrdquo Endocrine Reviews vol 30 no 4 pp 293ndash342 2009

[152] N Rokutanda T Iwasaki H Odawara et al ldquoAugmentationof estrogen receptor-mediated transcription by steroid andxenobiotic receptorrdquo Endocrine vol 33 no 3 pp 305ndash316 2008

[153] K Sakurai M Kawazuma T Adachi et al ldquoBisphenol A affectsglucose transport in mouse 3T3-F442A adipocytesrdquo BritishJournal of Pharmacology vol 141 no 2 pp 209ndash214 2004

[154] N A Reiss ldquoOntogeny and estrogen responsiveness of creatinekinase and glycolytic enzymes in brain and uterus of ratrdquoNeuroscience Letters vol 84 no 2 pp 197ndash202 1987

[155] R Eshtiaghi A Esteghamati and M Nakhjavani ldquoMenopauseis an independent predictor of metabolic syndrome in IranianwomenrdquoMaturitas vol 65 no 3 pp 262ndash266 2010

[156] J Munoz A Derstine and B A Gower ldquoFat distributionand insulin sensitivity in postmenopausal women influence ofhormone replacementrdquoObesity Research vol 10 no 6 pp 424ndash431 2002

[157] J H Pickar I Thorneycroft and M Whitehead ldquoEffects ofhormone replacement therapy on the endometrium and lipidparameters a review of randomized clinical trials 1985 to 1995rdquoAmerican Journal of Obstetrics and Gynecology vol 178 no 5pp 1087ndash1099 1998

[158] L Chmouliovsky F Habicht RW James T Lehmann A Cam-pana and A Golay ldquoBeneficial effect of hormone replacementtherapy onweight loss in obesemenopausal womenrdquoMaturitasvol 32 no 3 pp 147ndash153 1999

[159] A M Kenny A Kleppinger Y Wang and K M PrestwoodldquoEffects of ultra-low-dose estrogen therapy on muscle andphysical function in older womenrdquo Journal of the AmericanGeriatrics Society vol 53 no 11 pp 1973ndash1977 2005

[160] I H Thorneycroft R Lindsay and J H Pickar ldquoBody com-position during treatment with conjugated estrogens with andwithout medroxyprogesterone acetate analysis of the womenrsquosHealth Osteoporosis Progestin Estrogen (HOPE) trialrdquoAmer-ican Journal of Obstetrics and Gynecology vol 197 no 2 pp137e1ndash137e7 2007

[161] L B Tanko L Movsesyan O L Svendsen and C ChristiansenldquoThe effect of hormone replacement therapy on appendicularlean tissue mass in early postmenopausal womenrdquoMenopausevol 9 no 2 pp 117ndash121 2002

[162] M C Chu P Cosper G S Nakhuda and R A Lobo ldquoA com-parison of oral and transdermal short-term estrogen therapyin postmenopausal women with metabolic syndromerdquo Fertilityand Sterility vol 86 no 6 pp 1669ndash1675 2006

[163] S R Salpeter J M E Walsh T M Ormiston E Greyber N SBuckley and E E Salpeter ldquoMeta-analysis effect of hormone-replacement therapy on components of themetabolic syndromein postmenopausal womenrdquo Diabetes Obesity and Metabolismvol 8 no 5 pp 538ndash554 2006

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


emerging as a conceivable therapeutic challenge of the 21stcentury However environmental epigenetic factors may alsocontribute to obesity and a cultural bias that also hinderswomenrsquos efforts to combat obesity [33 34] Perhaps it is acombination of the aforementioned factors but the triggersfor obesity require further investigation To address thisgrowing problem improved understanding of how estrogenscontribute to energy balance lipid and glucose homeostasispromises to open a novel therapeutic applications for anincreasing large segment of the female populationThepoten-tial therapeutic relevance of estrogen physiology estrogenreceptors and the estrogen pathway will be discussed in thismanuscript

2 Methods

The study design was a review of existing published originalpapers and reviews We conducted this review of SSBs andhealth outcomes in accordance with the Preferred ReportingItems for Systematic Reviews and Meta-Analysis Statement(PRISMA) [35] PubMed publications until Nov 30 2013were taken into account

3 Estrogens and Estrogen Receptorsin Fat Metabolism

The hormones help integrate metabolic interaction amongmajor organs that are essential for metabolically intensiveactivities like reproduction and metabolic function Sexsteroids are required to regulate adipocyte metabolism andalso influence the sex-specific remodeling of particular adi-pose depots [36 37] In humans the factors that controlfat distribution are partially determined by sex hormonesconcentrations [38] Men on average have less total bodyfat but more centralintra-abdominal adipose tissue whereaswomen tend to have more total fat that favors glutealfemoraland subcutaneous depots [39] Weight and fat abdominaldistribution differ among women of reproductive age andmenopausal women [40 41] The decrease in estrogen levelsin menopausal women is associated with the loss of sub-cutaneous fat and an increase in abdominal fat [42] Theimportance of estrogens in subcutaneous fat accumulationis evident in fact estrogen hormonal therapy in men alsoincreases the amount of subcutaneous fat [43 44]

In humans 17-120573-estradiol (E2) is themost potent estrogenfollowed by estrone (E1) and estriol (E3) [45] The expressionof genes that encode the enzymes in estrogen syntheticpathway such as aromatase and reductive 17120573-hydroxysteroiddehydrogenases (17120573-HSD) is critical for E2 formation [46]Protein products of several genes with overlapping functionsmay confer reductive 17120573-HSD activities in peripheral tissues[47]

Estrogens function is mediated by nuclear receptors thatare transcription factors that belong to the superfamily ofnuclear receptors Two types of estrogen receptors (ERs) havebeen identified the alpha (ER120572) and beta (ER120573) receptors[48 49] The classical genomic action mechanism of ERaction typically occurs within hours leading to activation or

repression of target genes In this classical signaling pathwayligand activated ER dissociates from its chaperone heat-shock protein and binds as a dimer directly to an estrogenresponse element (ERE) in the promoter of target genes [50ndash52] although it was considered that the action of E2 wassubject to an action in gene expression regulation Recentlythere is increasing evidence of nonnuclear cytosolic or plasmamembrane-associate receptors that mediate nongenomic andrapid effects of several steroid hormones [53ndash55] In thismanner the traditional estrogen nuclear receptors have beenfound to function outside of the nucleus to direct nonge-nomic effects [56]

Several mechanisms of membrane-signaling activationcan explain rapid responses to E2These rapid actions includeactivation of kinase phosphatase and phospholipase thatcan mediate calcium-dependent signaling and can mediatedownstream nongenomic physiological responses such aseffects on cell cycle cell survival and energy metabolism[57 58]

Human subcutaneous and visceral adipose tissues expressboth ER120572 and ER120573 [59 60] whereas only ER120572 mRNAhas been identified in Brown adipose tissue [61 62] ER120572plays a major role in the activity of adipocytes and sexualdimorphism of fat distribution Female and male mice thatlack ER120572 have central obesity have severe insulin resistanceand are diabetic [63ndash65] Although not all studies are inagreement polymorphism of ER120572 in humans have beenassociated with risk factors for cardiovascular diseases [66]

Lipolysis in humans is controlled primarily by the actionof 120573-adrenergic receptors (lipolytic) and 1205722A-adrenergicreceptors (antilipolytic) [67] Estrogen seems to promote andmaintain the typical female type of fat distribution that ischaracterized by accumulation of adipose tissue especially inthe subcutaneous fat depot with only modest accumulationof intra-abdominal adipose tissue [68] Estradiol directlyincreases the number of antilipolytic 1205722A-adrenergic recep-tors in subcutaneous adipocytes [69] Visceral adipocytesexhibit a high 1205722A120573 ratio and these cells are stimulatedby epinephrine in contrast no effect of estrogen on 1205722A-adrenergic receptor mRNA expression was observed inadipocytes from the intra-abdominal fat depot [70]Howeverit is important to highlight that the effects of estrogensdiffers on the route of administration and the lipolyticinfluence of estrogens on fat accumulation affects specificregions of the body [71ndash73] E2 may also increase betaadrenoreceptor expression through ER120572 [74] These resultsprovide a mechanism insight for the effect of E2 on themaintenance of fat distributionwith an increased use of lipidsas energy source which partially promotes fat reduction inabdominal fat This effect occurs via the facilitation of fatoxidation in the muscle by the inhibition of lipogenesis inthe liver and muscle through the regulation of peroxisomeproliferator-activated receptor 120574 (PPAR120574) and an increase inLPL expression [75ndash77] E2 also increases muscle oxidativecapacity by means of the regulation of acyl-CoA oxidase anduncoupling proteins (UCP2-UCP3) which enhances fattyacid uptakewithout lipid accumulation [78 79]Therefore E2improves fat oxidation through the phosphorylation of AMP-kinase (AMPK) in muscle and myotubes in culture [80 81]


ER120572

ER120572

ER120572

120573-AR

(SREBP1c)Lipolysis

LCFA

Adipogenesis

E2Epinephrine

LPLE2

UCP1

E2

PGC1-120572

AMPk-P









Reduce food intake


POMC VMHSF-1


HO

OH




TCA cycle


Acetyl-CoA

Citrate synthase

Aconitase



thiokinase


Fumarase

Malatedehydrogenase





















OH

HH

HO

H

ClClCl

C

CH

ClCl

OHHO

HO O

OOHOH

Genistein

Bisphenol A

DDT

EstradiolEndogenous

estrogen

Pesticide

Plasticscomponent

Phytoestrogen





9 Conclusion




References














































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ER120572

ER120572

ER120572

120573-AR

(SREBP1c)Lipolysis

LCFA

Adipogenesis

E2Epinephrine

LPLE2

UCP1

E2

PGC1-120572

AMPk-P









Reduce food intake


POMC VMHSF-1


HO

OH




TCA cycle


Acetyl-CoA

Citrate synthase

Aconitase



thiokinase


Fumarase

Malatedehydrogenase





















OH

HH

HO

H

ClClCl

C

CH

ClCl

OHHO

HO O

OOHOH

Genistein

Bisphenol A

DDT

EstradiolEndogenous

estrogen

Pesticide

Plasticscomponent

Phytoestrogen





9 Conclusion




References














































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Reduce food intake


POMC VMHSF-1


HO

OH




TCA cycle


Acetyl-CoA

Citrate synthase

Aconitase



thiokinase


Fumarase

Malatedehydrogenase





















OH

HH

HO

H

ClClCl

C

CH

ClCl

OHHO

HO O

OOHOH

Genistein

Bisphenol A

DDT

EstradiolEndogenous

estrogen

Pesticide

Plasticscomponent

Phytoestrogen





9 Conclusion




References














































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































OH

HH

HO

H

ClClCl

C

CH

ClCl

OHHO

HO O

OOHOH

Genistein

Bisphenol A

DDT

EstradiolEndogenous

estrogen

Pesticide

Plasticscomponent

Phytoestrogen





9 Conclusion




References














































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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