REPRODUCTIONREVIEW PROOF ONLY The role of sex steroids in white adipose tissue adipocyte function A E Newell-Fugate Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA Correspondence should be addressed to A E Newell-Fugate; Email: [email protected] Abstract With the increasing knowledge that gender influences normal physiology, much biomedical research has begun to focus on the differential effects of sex on tissue function. Sexual dimorphism in mammals is due to the combined effects of both genetic and hormonal factors. Hormonal factors are mutable particularly in females in whom the estrous cycle dominates the hormonal milieu. Given the severity of the obesity epidemic and the fact that there are differences in the obesity rates in men and women, the role of sex in white adipose tissue function is being recognized as increasingly important. Although sex differences in white adipose tissue distribution are well established, the mechanisms affecting differential function of adipocytes within white adipose tissue in males and females remain largely understudied and poorly understood. One of the largest differences in the endocrine environment in males and females is the concentration of circulating androgens and estrogens. This review examines the effects of androgens and estrogens on lipolysis/lipogenesis, adipocyte differentiation, insulin sensitivity and adipokine production in adipocytes from white adipose tissue with a specific emphasis on the sexual dimorphism of adipocyte function in white adipose tissue during both health and disease. Reproduction (2017) 153 R133–R149 Introduction Gynecoid adipose tissue distribution is associated with lower risks for type II diabetes and coronary artery disease Historically, the effects of gender have been largely (Manolopoulos et al. 2010). Recent evidence suggests ignored across biomedical research. Subsequent to this that sex-specific single nucleotide polymorphisms practice, studies utilizing immortalized cell lines, single- (SNPs) help direct fat distribution in males and sex animal models or human patients representing only females and epigenetically regulate lipid homeostasis one sex have resulted in the inability to determine (Sung et al. 2016). Visceral adipocytes exhibit similar whether research findings are applicable to both sexes basal lipolysis but higher catecholamine-stimulated (Johnson et al. 2014). In recent years, concerns initially lipolysis compared to subcutaneous adipocytes in raised about the lack of women in clinical studies both sexes (Tchernof et al. 2006, Boivin et al. 2007). (Kim et al. 2010) have resulted in the National Institutes Lipoprotein lipase (LPL) activity and glucose uptake are of Health (NIH) requiring sex balance in research lower in visceral adipocytes than those in subcutaneous involving cells and animal models (Clayton & Collins adipocytes in women who also have smaller adipocytes, 2014). Furthermore, sex differences in the relative risk but is similar among adipocytes from these two white for diseases such as cancer, obesity, coronary heart adipose tissue (WAT) depots in men (Edens et al. 1993, disease and autoimmune diseases are well established Boivin et al. 2007). Differences in adipocyte function (Becker et al. 2005). within different WAT depots may be related to the Sexual dimorphism in mammals is the result of differences in WAT distribution in women and men. both genetic and hormonal factors (Money & Ehrhardt Disease states in women associated with elevated 1972). Genetic factors derived from chromosomes circulating androgen concentrations such as are relatively permanent, whereas hormonal factors polycystic ovary syndrome (PCOS) or congenital are mutable, particularly in females in whom the adrenal hyperplasia may result in android adipose hypothalamic–pituitary–gonadal axis and the menstrual tissue accumulation and, subsequently, an increased cycle predominantly control the hormonal milieu propensity for insulin resistance and atherosclerosis (Christensen et al. 2012). Women have a higher (Sirmans & Pate 2014). By contrast, overweight men percentage body fat than men and tend to distribute with visceral adipose tissue accumulation are at risk for their adipose tissue in the hips and thighs (‘gynecoid’), hypogonadism, low androgen levels and type II diabetes whereas men tend to distribute their adipose tissue (Dandona & Dhindsa 2011). Furthermore, menopause, abdominally (‘android’) (Karastergiou et al. 2012). © 2017 Society for Reproduction and Fertility DOI: 10.1530/REP-16-0417 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/27/2021 08:19:27AM via free access 10.1530/REP-16-0417 R134 A E Newell-Fugate which is due to the onset of ovarian inactivity and its effects through binding to either classical estrogen results in decreased PROOFestrogen and progesterone levels, receptors ONLY (ER), which are nuclear transcription factors is accompanied by increases in overall adiposity, expressed widely throughout the adipose tissue particularly due to visceral adipose tissue accumulation compartment (Mizutani et al. 1994, Dieudonné et al. (Tchernof & Poehlman 1998). The aforementioned body 1998), or to non-classical ER like G-protein-coupled transitions and disease states underscore the importance estrogen receptor (GPER), which are membrane-bound of sex steroid hormones to WAT adipocyte function. receptors (Prossnitz & Barton 2011). There are two Although sex differences in WAT distribution are well classes of classical ERs, ER alpha (ERα) and ER beta established, the mechanisms affecting differential WAT (ERβ), each of which has a distinct tissue distribution adipocyte function in males and females are poorly (Koehler et al. 2005). In addition to differential tissue understood. Given the severity of the obesity epidemic expression, the ligand binding domains of ERα and ERβ and the fact that there are differences in the rate at which are unique, which allows selective ligands to target obesity affects men and women (Flegal et al. 2016) one or the other pathway (Koehler et al. 2005). With ( et al. 2016), the role of sex in WAT adipocyte function respect to reproductive tissues, ERα is uterotropic and is recognized as increasingly important. Although other found in the ovarian stroma and breast, whereas ERβ factors besides sex steroid levels vary and account for is in the ovarian granulosa cells (Korach et al. 2003). differences between WAT adipocyte function in males and Current literature suggests that ERα modulates anti- females, sex steroids play a central role in the regulation lipogenesis, insulin sensitivity and glucose tolerance, of many tissues in the body (Wierman 2007). Additionally, and reduction of body weight and WAT mass (Blüher it is likely that sex differences in cell types other than 2013). In contrast, ERβ appears to be detrimental for adipocytes within WAT also account for differences in the maintenance of glucose and lipid homeostasis metabolism between males and females. However, this (Foryst-Ludwig & Kintscher 2010). Recent evidence review focuses on the effect of sex steroids (androgens and also indicates a role for the non-genomic regulation estrogens) on WAT adipocyte function including lipolysis/ of WAT lipogenesis by GPER, but the findings between lipogenesis, adipocyte differentiation, insulin sensitivity publications differ (Haas et al. 2009, Isensee et al. 2009, and adipokine production/secretion. Particular emphasis Mårtensson et al. 2009, Sharma et al. 2013). Several is paid in this review to the sexual dimorphism of WAT studies have demonstrated that male GPER-deficient adipocyte function in the context of steroid hormones in (GPERKO) mice suffer from increased WAT mass and both health (i.e. menopause) and disease (i.e. polycystic decreased insulin sensitivity, whereas female GPERKO ovary syndrome in women, hypogonadism in men). mice have decreased weights (Mårtensson et al. 2009, Sharma et al. 2013). Other studies have shown that both male and female GPERKO mice have increased WAT, Estrogens particularly in the visceral compartment (Haas et al. Lipolysis and lipogenesis 2009). Finally, other studies have found no differences in body weight and adiposity between GPERKO and Lipolysis and lipogenesis of adipose tissue assists wild-type male or female mice fed either a control with energy release and energy storage in the body or high-fat diet (Isensee et al. 2009). Research using (Thomas et al. 1979) (Fig. 1). Estradiol (E2) renders knock-out rodent models has demonstrated that both Figure 1 Overview of adipocyte metabolism. After a meal, energy enters the adipocyte through several mechanisms: 1) direct absorption of fatty acids (FA) from the blood stream, 2) uptake of glucose through GLUT4 receptors on the adipocyte cell membrane and 3) cleavage of triglycerides (TG) into fatty acids via lipoprotein lipase (LPL) made by the adipocyte. Catecholamines stimulate release of fatty acids from triglycerides in the triglyceride pool by stimulating hormone- sensitive lipase (HSL; 4). Insulin stimulates uptake of glucose via GLUT4 (2) but inhibits lipolysis via HSL (5). Fatty acids can be released from the adipocyte after lipolysis (6). Reproduction (2017) 153 R133–R149 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/27/2021 08:19:27AM via free access Sex steroids and adipocyte function R135 cytosolic and membrane-bound sex steroid receptors It is