Estrogen Regulation of Adiposity and Fuel Partitioning

Abstract

Menopause is associated with increased adiposity and greater risk of metabolic disease. In the ovariectomized (OVX) rodent model of menopause, increased adiposity is prevented by estrogen (E2) replacement, reflecting both anorexigenic and potentially metabolic actions of E2. To elucidate metabolic and molecular mechanisms by which E2 regulates fat storage and fat mobilization independently of reduced energy intake, C57 BL/6 mice were ovariectomized, randomized to estrogen (OVX-E2) or control pellet implants (OVX-C), and pairfed for 40 days. E2 treatment was associated with reduced adipose mass and adipocyte size and down-regulation of lipogenic genes in adipocytes under the control of sterol-regulatory element-binding protein 1c. Adipocytes of OVX-E2 mice contained >3-fold more perilipin protein than adipocytes of pairfed control (OVX) mice, and this difference was associated with enhanced ex vivo lipolytic response to catecholamines and with greater levels of serum-free fatty acids following fasting. As in adipose tissue, E2 decreased the expression of lipogenic genes in liver and skeletal muscle. In the latter, E2 appears to promote the partitioning of free fatty acids toward oxidation and away from triglyceride storage by up-regulating the expression of peroxisome proliferation activator receptor-δ and its downstream targets and also by directly and rapidly activating AMP-activated protein kinase. Thus, novel genomic and non-genomic actions of E2 promote leanness in OVX mice independently of reduced energy intake. Menopause is associated with increased adiposity and greater risk of metabolic disease. In the ovariectomized (OVX) rodent model of menopause, increased adiposity is prevented by estrogen (E2) replacement, reflecting both anorexigenic and potentially metabolic actions of E2. To elucidate metabolic and molecular mechanisms by which E2 regulates fat storage and fat mobilization independently of reduced energy intake, C57 BL/6 mice were ovariectomized, randomized to estrogen (OVX-E2) or control pellet implants (OVX-C), and pairfed for 40 days. E2 treatment was associated with reduced adipose mass and adipocyte size and down-regulation of lipogenic genes in adipocytes under the control of sterol-regulatory element-binding protein 1c. Adipocytes of OVX-E2 mice contained >3-fold more perilipin protein than adipocytes of pairfed control (OVX) mice, and this difference was associated with enhanced ex vivo lipolytic response to catecholamines and with greater levels of serum-free fatty acids following fasting. As in adipose tissue, E2 decreased the expression of lipogenic genes in liver and skeletal muscle. In the latter, E2 appears to promote the partitioning of free fatty acids toward oxidation and away from triglyceride storage by up-regulating the expression of peroxisome proliferation activator receptor-δ and its downstream targets and also by directly and rapidly activating AMP-activated protein kinase. Thus, novel genomic and non-genomic actions of E2 promote leanness in OVX mice independently of reduced energy intake. Estrogen (E2) 3The abbreviations used are:E217β-estradiolACCacetyl-CoA carboxylaseACOXacyl-CoA oxidaseAMPKAMP-activated protein kinaseFASfatty acid synthaseFFAfree fatty acidsHSLhormone-sensitive lipaseLPLlipoprotein lipaseLXR-αliver X receptor-αOVXovariectomyPPARperoxisome proliferation activator receptorSREBP-1csterol regulatory element-binding protein 1cUCPuncoupling proteinERestrogen receptorEREestrogen response element is a steroid hormone whose actions are mediated by genomic and non-genomic mechanisms (1Bjornstrom L. Sjoberg M. Mol. Endocrinol. 2005; 19: 833-842Crossref PubMed Scopus (1037) Google Scholar). The classical genomic mechanism of E2 action involves activation of its nuclear receptor (estrogen receptor (ER) α or β), receptor dimerization, and subsequent binding to ER response elements (EREs) located in the promoters of target genes. More recently, E2 has been shown to have rapid, non-genomic biological effects, believed to be mediated through membrane-bound subpopulations of ER-α and ER-β and/or the newly described G protein-coupled receptor 30 (GPRC30) (2Pappas T. Gametchu B. Watson C. FASEB J. 1995; 9: 404-410Crossref PubMed Scopus (477) Google Scholar, 3Razandi M. Pedram A. Greene G.L. Levin E.R. Mol. Endocrinol. 1999; 13: 307-319Crossref PubMed Scopus (1008) Google Scholar, 4Kelly M.J. Levin E.R. Trends Endocrinol. Metab. 2001; 12: 152-156Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar, 5Evinger Spaceiiiqq A.J. Levin E.R. Steroids. 2005; 70: 361-363Crossref PubMed Scopus (95) Google Scholar, 6Thomas P. Pang Y. Filardo E.J. Dong J. Endocrinology. 2005; 146: 624-632Crossref PubMed Scopus (1171) Google Scholar, 7Revankar C.M. Cimino D.F. Sklar L.A. Arterburn J.B. Prossnitz E.R. Science. 2005; 307: 1625-1630Crossref PubMed Scopus (1866) Google Scholar). Here, we provide evidence that E2 has significant effects on energy metabolism through both genomic and non-genomic mechanisms and that these effects collectively promote leanness in pairfed ovariectomized (OVX) mice. 17β-estradiol acetyl-CoA carboxylase acyl-CoA oxidase AMP-activated protein kinase fatty acid synthase free fatty acids hormone-sensitive lipase lipoprotein lipase liver X receptor-α ovariectomy peroxisome proliferation activator receptor sterol regulatory element-binding protein 1c uncoupling protein estrogen receptor estrogen response element Systemic loss of estrogen at menopause is associated with increased adiposity, which is implicated in the elevated risk of age-related metabolic disease in women (8Tchernof A. Desmeules A. Richard C. Laberge P. Daris M. Mailloux J. Rheaume C. Dupont P. J. Clin. Endocrinol. Metab. 2004; 89: 3425-3430Crossref PubMed Scopus (124) Google Scholar, 9Tchernof A. Poehlman E. Obes. 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For example, women randomized to hormone replacement therapy in the Women's Health Initiative were leaner, more insulin sensitive, and less likely to develop Type 2 diabetes than women randomized to placebo (20Margolis K.L. Bonds D.E. Rodabough R.J. Tinker L. Phillips L.S. Allen C. Bassford T. Burke G. Torrens J. Howard B.V. Diabetologia. 2004; 47: 1175-1187Crossref PubMed Scopus (469) Google Scholar). These observations suggest an important, beneficial role for estrogen in energy regulation. Moreover, the beneficial metabolic role of estrogen may not be limited to women (21Herrmann B.L. Janssen O.E. Hahn S. Broecker-Preuss M. Mann K. Horm. Metab. Res. 2005; 37: 178-183Crossref PubMed Scopus (38) Google Scholar, 22Herrmann B.L. Saller B. Janssen O.E. Gocke P. Bockisch A. Sperling H. Mann K. Broecker M. J. Clin. Endocrinol. Metab. 2002; 87: 5476-5484Crossref PubMed Scopus (198) Google Scholar). The molecular and cell-biological mechanisms underlying the metabolic actions of estrogen are poorly understood. Much of our current view of the actions of estrogen on adiposity and metabolism derive from the ovariectomized rodent model of menopause. OVX rodents rapidly become obese and E2 administration prevents the increase in body fat (23Cooke P.S. Naaz A. Exp. Biol. Med. (Maywood). 2004; 229: 1127-1135Crossref PubMed Scopus (287) Google Scholar, 24Lazzarini S.J. Wade G.N. Am. J. Physiol. 1991; 260: R47-R51PubMed Google Scholar, 25Wade G.N. Gray J.M. Bartness T.J. Int. J. Obes. 1985; 9: 83-92PubMed Google Scholar, 26Shimomura K. Shimizu H. Tsuchiya T. Abe Y. Uehara Y. Mori M. Endocr. J. 2002; 49: 417-423Crossref PubMed Scopus (28) Google Scholar, 27Richard D. Am. J. Physiol. 1986; 250: R245-R249Crossref PubMed Google Scholar, 28Meli R. Pacilio M. Raso G.M. Esposito E. Coppola A. Nasti A. Di Carlo C. Nappi C. Di Carlo R. Endocrinology. 2004; 145: 3115-3121Crossref PubMed Scopus (170) Google Scholar). However, ovariectomy induces hyperphagia in rodents, and this hyperphagia is itself ameliorated by E2 replacement (25Wade G.N. Gray J.M. Bartness T.J. Int. J. Obes. 1985; 9: 83-92PubMed Google Scholar, 26Shimomura K. Shimizu H. Tsuchiya T. Abe Y. Uehara Y. Mori M. Endocr. J. 2002; 49: 417-423Crossref PubMed Scopus (28) Google Scholar, 27Richard D. Am. J. Physiol. 1986; 250: R245-R249Crossref PubMed Google Scholar, 28Meli R. Pacilio M. Raso G.M. Esposito E. Coppola A. Nasti A. Di Carlo C. Nappi C. Di Carlo R. Endocrinology. 2004; 145: 3115-3121Crossref PubMed Scopus (170) Google Scholar, 29Liang Y.Q. Akishita M. Kim S. Ako J. Hashimoto M. Iijima K. Ohike Y. Watanabe T. Sudoh N. Toba K. Yoshizumi M. Ouchi Y. Int. J. Obes. Relat. Metab. Disord. 2002; 26: 1103-1109Crossref PubMed Scopus (136) Google Scholar). Thus, reduced energy intake contributes to reduced adiposity in E2-treated OVX rodents (OVX-E2). This differential energy intake confounds our elucidation of how and to what extent, reduced adiposity in OVX-E2 rodents reflects estrogen actions on metabolically critical tissues (adipose, liver, and muscle). Employing a pairfeeding paradigm, the present study defines for the first time how estrogen protects against increased adiposity in OVX mice independently of differences in energy intake. We demonstrate that estrogen inhibits lipogenic gene expression, promotes catecholamine-stimulated lipolysis in adipocytes, and stimulates lipid-oxidative pathways in muscle. These metabolic effects reflect the genomic actions of estrogen on SREBP-1c and PPAR-δ-regulated gene expression, as well as novel, non-genomic estrogen actions on AMPK-activated protein kinase (AMPK). Animals—Female C57BL/6 mice were obtained from Taconic Laboratories (Germantown, NY). All animals were housed in an AAALAC-approved animal facility with 12-h light/dark cycles, given free access to water, and fed standard rodent chow (PROLAB, Syracuse, NY). Bilateral ovariectomy was performed on 10-week-old mice as previously described (30Sullivan Jr., T.R. Karas R.H. Aronovitz M. Faller G.T. Ziar J.P. Smith J.J. O'Donnell Jr., T.F. Mendelsohn M.E. J. Clin. Investig. 1995; 96: 2482-2488Crossref PubMed Scopus (238) Google Scholar). After a 7-day recovery, mice were randomized to either placebo or E2 (OVX-E2) of 17β-estradiol and This and levels of estrogen in ovariectomized mice R.H. H. G. Aronovitz M.J. C. Mendelsohn M.E. Res. 2001; 89: PubMed Scopus Google Scholar). mice were to OVX-E2 mice. To mice were housed and fed the intake of the OVX-E2 from the intake and body were the to tissue mice were fed at and was at for an and Systemic 40 of was obtained from mice by under fatty acids were a was by and and were a was a 2 and and fat were and a of fat was the previously described Smith S.J. C. D. H. Am. J. Physiol. 2002; PubMed Scopus (98) Google adiposity adipocytes were and as previously described C. J. Biol. 1985; 260: Full Text PDF PubMed Google with The were and at with was were in to lipolysis under and was as the a P. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). was of and adipocyte of fat was to previously M. S. Am. J. Physiol. PubMed Scopus Google Scholar). was by of from Adipocytes were adipocytes a and a was of and adipocyte M. S. Am. J. Physiol. PubMed Scopus Google Scholar). Type were and as previously described Mol. 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A. and which as a was by the of of on was in of skeletal and/or following in and were to and with against and tissue liver, and were in and in and at was from of tissue was by and was from of a was performed on in on an in a were or from previously on were a critical 2001; PubMed Scopus Google with the of target gene to the of control genes and difference was by are as and were by effects were by of for was as Estrogen and in mice (OVX-E2) less on as with fed After the of by OVX-E2 mice on the body and of were in OVX and OVX-E2 mice. was difference in or was not by treatment was in OVX-E2 mice, the of estrogen treatment in this study body and were adiposity was reduced in OVX-E2 mice The associated in adipose mass were in both and and the was not significant in fat mass reflects both adipocyte and adipocyte the a of fat adipose tissue mass in OVX-E2 mice was with in adipocyte that estrogen effects on adipose mass are mediated in by estrogen effects on adipocyte size These demonstrate that estrogen treatment promotes adipocytes and reduced adipose mass independently of reduced energy intake in OVX mice. 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Jr., 2005; PubMed Scopus (98) Google of in by as a fat and of in of which prevents the of a for in and for to the for Here, we demonstrate for the first time that estrogen rapidly in skeletal muscle. are to the of E2 in skeletal is mediated through the newly described G protein-coupled receptor 30 C.M. Cimino D.F. Sklar L.A. Arterburn J.B. Prossnitz E.R. Science. 2005; 307: 1625-1630Crossref PubMed Scopus (1866) Google or estrogen In to fat E2 appears to on metabolic tissues tissue, and to prevent Estrogen treatment decreased expression of SREBP-1c in adipose tissue, and liver, and adipose tissue expression of a of SREBP-1c E. S. J. 2002; PubMed Scopus Google and SREBP-1c promotes the expression of lipogenic genes as and and 2002; PubMed Scopus Google Scholar). of expression likely to a in adipose tissue SREBP-1c expression, is not reduced in or liver in response to E2. This an mechanism by which E2 regulates expression of SREBP-1c and its downstream is that E2 directly regulates which an in its A. S. A. Liu E.T. Res. 2003; PubMed Scopus Google Scholar). In as SREBP-1c expression is by G. R. Y. Y. J. M. J. T. N. N. D.E. J. Clin. Investig. 2001; PubMed Scopus Google SREBP-1c expression in the present study may reflect the novel non-genomic effects of E2 on activation reduced expression of lipogenic genes may reflect the partitioning of toward fat oxidation the of for In either reduced expression of SREBP-1c target genes is to with in and adipocyte In of adipose tissue expression in adipocytes by the of from the for may also to in adipose tissue mass and adipocyte estrogen administration has previously been shown to increase the lipolytic in vivo C. R. J. G. R. Endocrinology. PubMed Scopus Google Scholar). This is likely at in by in adipose tissue S.J. Wade G.N. Am. J. Physiol. 1991; 260: R47-R51PubMed Google Scholar). In and Wade S.J. Wade G.N. Am. J. Physiol. 1991; 260: R47-R51PubMed Google that adipose tissue in adipose tissue mass by Here, we a novel mechanism by which estrogen potentially promotes elevated of adipocyte we demonstrate that E2 treatment levels of the a of lipolysis L. P. M. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus (198) Google Scholar). Adipocytes with perilipin expression enhanced to to in the effects of E2 on adipose tissue In we demonstrate for the first time that E2 adiposity and adipocyte size in OVX mice of differences in energy intake. We novel genomic and non-genomic pathways that promote fat prevent and These metabolic effects reflect the genomic actions of estrogen on SREBP-1c and PPAR-δ-regulated gene expression, as well as novel, non-genomic estrogen actions on