The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis

R E V I E W The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis Franck Mauvais-Jarvis, Deborah J. Clegg, and Andrea L. Hevener Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet ␤-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders. (Endocrine Reviews 34: 309 –338, 2013) I. Contribution of Sex Hormones to Metabolic Diseases II. Origin of Circulating and Tissue Estrogens in Males and Females III. Mechanisms of Estrogen Receptor (ER) Action IV. Evolutionary Importance of ER in Energy Metabolism V. ER and Control of Energy Intake and Expenditure A. Estrogen action in the hypothalamus in relation to energy balance B. ER␣ in the ARC and control of food intake C. ER␣ in the ventromedial hypothalamus and control of energy expenditure D. ER␣ in the brainstem and control of food intake E. Estrogen interaction with leptin F. Estrogen interaction with neuropeptide-1 VI. ER and Regulation of Adipose Tissue Distribution A. Intra-abdominal adipose tissue and the metabolic syndrome B. Subcutaneous adipose tissue and lipid storage C. ER␣ and adipose tissue distribution D. ER and adipose tissue lipid metabolism VII. ER and Insulin Sensitivity A. Estrogens and insulin sensitivity B. ER␣ in relation to skeletal muscle glucose transporter GLUT4 C. ER␣ in relation to skeletal muscle fatty acid metabolism and inflammation ISSN Print 0163-769X ISSN Online 1945-7189 Printed in U.S.A. Copyright © 2013 by The Endocrine Society Received August 31, 2012. Accepted December 12, 2012. First Published Online March 4, 2013 doi: 10.1210/er.2012-1055 D. ERs and insulin sensitivity in the liver VIII. ER␣ and Functioning of Macrophages and Immune Cells IX. ER in Relation to Pancreatic ␤-Cell Function X. Estrogen Sulfotransferase and Metabolism XI. Estrogen Therapy and Metabolism A. Relation of route of estrogen administration and metabolism B. Effect of selective estrogen receptor modulators and aromatase inhibitors on metabolism XII. Conclusions and Perspectives I. Contribution of Sex Hormones to Metabolic Diseases n 1941, estrogen products were approved by the US Food and Drug Administration as a hormone supplement to treat postmenopausal symptoms. In the following I Abbreviations: AgRP, Agouti-related peptide; AI, aromatase inhibitor; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; CCK, cholecystokinin; CEE, conjugated equine estrogen; CoA, coenzyme A; E1, estrone; E2, 17␤-estradiol; ER, estrogen receptor; ERE, estrogen response element; EST, estrogen sulfotransferase; FAS, fatty acid synthase; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; GLUT4, glucose transporter 4; GPER, G protein-coupled ER; HFD, high fat diet; HGP, hepatic glucose production; HRT, hormone replacement therapy; KO, knockout; LDL, low-density lipoprotein; leprb, leptin receptor; LPL, lipoprotein lipase; LXR, liver X receptor; MC4, melanocortin 4; MEF2, myocyte enhancer factor 2; MERKO, muscle-specific ER␣KO (mice); NPY, neuropeptide Y; NTS, nucleus tractus solitarius; OVX, ovariectomy; POMC, pro-opiomelanocortin; PPAR, peroxisome proliferator-activated receptor; PPT, propylpyrazole triol; SERM, selective estrogen receptor modulator; SF1, steroidogenic factor-1; SREBP-1c, sterol regulatory elementbinding protein 1c; STAT3, signal transducer and activator of transcription 3; STZ, streptozotocin; TSEC, tissue-selective estrogen complex; VMH, ventromedial hypothalamus; VMN, ventromedial nucleus; WAT, white adipose tissue. Endocrine Reviews, June 2013, 34(3):309 –338 edrv.endojournals.org 309 Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine (F.M.-J.), and Comprehensive Center on Obesity (F.M.-J.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Internal Medicine (D.J.C.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Medicine (A.L.H.), Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, California 90095 310 Mauvais-Jarvis et al Estrogens in Energy Balance and Glucose Homeostasis II. Origin of Circulating and Tissue Estrogens in Males and Females In healthy premenopausal women, 17␤-estradiol (E2), the main circulating estrogen, is produced by the ovaries after aromatization of androstenedione to estrone (E1) and subsequent conversion of E1 to E2. Among women with normal menstrual cycles, E2 functions as a circulating hormone that acts on distant target tissues (Figure 1A). In postmenopausal women, however, when the ovaries fail to produce E2 and in men—who have naturally low levels of circulating E2—E2 does not function as a circulating hormone; rather, it is synthesized in extragonadal sites such as breast, brain, muscle, bone, and adipose tissue where it acts locally as a paracrine or intracrine factor (8). Therefore, among both postmenopausal women and men, the determinant of E2 action is not circulating estrogens; rather, E2 function depends on estrogen biosynthesis from a circulating source of androgens (Figure 1B). Consequently, in these individuals, a major driver of E2 action is the aromatization of androgens to estrogens (8). Thus, tissue metabolism or inactivation of E2 is also an essential parameter controlling cellular estrogenic action (9). Tissue estrogen sulfotransferase (EST) is a critical mediator of estrogen action (Figure 1, A and B). EST is a cytosolic enzyme that provides a molecular switch in target cells that inhibits estrogen activity by conjugating a sulfonate group to estrogens, thereby preventing binding to estrogen receptors and enhancing urinary excretion of the hormone (10). III. Mechanisms of Estrogen Receptor (ER) Action Early studies of the reproductive actions of estrogens led to the establishment of a paradigm in which classical nuclear ERs acted as ligand-activated transcription factors (11). ER modulation of gene transcription is a highly dynamic process. The ER exists in 2 main forms, ER␣ and ER␤, each of which has multiple isoforms and exhibit distinct tissue expression patterns and functions ( (...truncated)