Elsevier

Molecular and Cellular Endocrinology

Volume 402, 15 February 2015, Pages 113-119
Molecular and Cellular Endocrinology

Review
The sexual dimorphism of obesity

https://doi.org/10.1016/j.mce.2014.11.029Get rights and content

Abstract

The NIH has recently highlighted the importance of sexual dimorphisms and has mandated inclusion of both sexes in clinical trials and basic research. In this review we highlight new and novel ways sex hormones influence body adiposity and the metabolic syndrome. Understanding how and why metabolic processes differ by sex will enable clinicians to target and personalize therapies based on gender. Adipose tissue function and deposition differ by sex. Females differ with respect to distribution of adipose tissues, males tend to accrue more visceral fat, leading to the classic android body shape which has been highly correlated to increased cardiovascular risk; whereas females accrue more fat in the subcutaneous depot prior to menopause, a feature which affords protection from the negative consequences associated with obesity and the metabolic syndrome. After menopause, fat deposition and accrual shift to favor the visceral depot. This shift is accompanied by a parallel increase in metabolic risk reminiscent to that seen in men. A full understanding of the physiology behind why, and by what mechanisms, adipose tissues accumulate in specific depots and how these depots differ metabolically by sex is important in efforts of prevention of obesity and chronic disease. Estrogens, directly or through activation of their receptors on adipocytes and in adipose tissues, facilitate adipose tissue deposition and function. Evidence suggests that estrogens augment the sympathetic tone differentially to the adipose tissue depots favoring lipid accumulation in the subcutaneous depot in women and visceral fat deposition in men. At the level of adipocyte function, estrogens and their receptors influence the expandability of fat cells enhancing the expandability in the subcutaneous depot and inhibiting it in the visceral depot. Sex hormones clearly influence adipose tissue function and deposition, determining how to capture and utilize their function in a time of caloric surfeit, requires more information. The key will be harnessing the beneficial effects of sex hormones in such a way as to provide ‘healthy’ adiposity.

Introduction

Over the past 20 years, adult and childhood obesity rates have doubled, while adolescent obesity has tripled (Ford et al., 2014). Two-thirds of Americans are currently at-risk for obesity related mortality or morbidity however this differs by sex. While the connection between obesity and risk of heart disease, hypertension, cancer, stroke, and diabetes is well established in men, it is less so for women and the mechanisms underlying these sexually dimorphic influences remain poorly understood. Over the past decade adipose tissues have been determined to be more than a storage vessel for triglycerides, rather, these tissues actively contribute to metabolic homeostasis by secreting a wide variety of signaling molecules and hormones. An often underappreciated finding is that adipose tissue function and deposition differ by sex. Females have an overall higher total body fat content when compared to men. Importantly, females differ with respect to distribution of adipose tissues, males tend to accrue more visceral fat, leading to the classic android body shape which has been highly correlated to increased cardiovascular risk; whereas females accrue more fat in the subcutaneous depot prior to menopause, a feature associated with protection from the negative consequences associated with obesity and the metabolic syndrome (Fig. 1). After menopause, fat deposition and accrual shift to favor the visceral depot. This shift is accompanied by a parallel increase in metabolic risk reminiscent to that seen in men. A full understanding of the physiology behind why, and by what mechanisms, adipose tissues accumulate in specific depots and how these depots differ metabolically by sex is important in efforts of prevention of obesity and chronic disease. A review of sex differences in obesity/adipose tissue distribution is timely given that obesity has recently been classified as a disease, and that the National Institutes of Health has made it mandatory to explore gender differences in disease states.

Section snippets

Estrogens and adiposity

Obesity is influenced by a number of variables such as ethnicity, socioeconomic status and education which makes it difficult in humans to determine whether a biological difference per se exists regarding the propensity to gain weight between men and women. By contrast, in animal models where non-biological factors are excluded, studies suggest the propensity toward development of obesity differs between the sexes and this is directly due to sex hormones. For example, female rats gain less

Sexual dimorphism and fat distribution

Premenopausal women tend to store fat on the hips, thighs and buttocks, giving them a pear shape also called gynoid, or gluteal–femoral pattern of adipose tissue distribution. Men accumulate fat predominately in the abdominal region giving them an apple shape also referred to as android, or abdominal pattern of fat accrual (Fig. 1). Even lean men carry a greater proportion of their body fat in the visceral depot as compared to lean women.

Differences in adipose tissue distribution are tied to

Visceral vs subcutaneous adipose tissue and metabolic function

Visceral fat is a source of proinflammatory cytokines that contribute to insulin resistance. In addition, the high lipolytic rate of visceral fat generates large amounts of free fatty acids that are delivered to the liver causing increased hepatic glucose production, hyperinsulinemia, and other features of the metabolic syndrome (Shulman, 2014). By contrast, accumulation of fat in the subcutaneous depot is an independent predictor of lower cardiovascular and diabetes-related mortality, and

Visceral and subcutaneous adipocytes differ

Accumulating evidence suggests obesity complications result from the inability of fat cells to expand and safely store lipids (Fig. 2), which leads to ectopic deposition of lipids in other tissues termed lipotoxicity which results in insulin resistance (Shulman, 2014). Expansion of fat mass can occur either by an increase in volume of preexisting adipocytes (hypertrophy) or by hyperplasia in which an increase in fat mass occurs through recruitment of new preadipocytes. When fat cells surpass

Estrogens and ‘browning’ of adipose tissues

Estrogens not only influence adipose tissue hyperplasia/hypertrophy and distribution, but they also influence the metabolic activity of adipose tissues by regulating ‘browning’, or enhancing the metabolic activity of adipose tissues (Fig. 3). Brown adipose tissue is metabolically more active due to the increased number of mitochondria. Recent data suggest the metabolic rate per kilogram adipose tissue is higher in women than men due to higher levels of brown adipose tissue in women and

Teleological explanation for sex differences in adipose tissue deposition

The evolutionary basis as to why women preferentially store fat in the gluteal–femoral region is not known; however, one hypothesis is that women accumulate energy reserves in the subcutaneous depot to prepare for adipose tissue mobilization required for lactation. Longitudinal studies of skin-fold thickness during pregnancy and lactation consistently show fat accumulation in the supra-iliac and mid-thigh regions (subcutaneous adipose tissue depots) during pregnancy, which is mobilized

Summary

In this review we have demonstrated that estrogens, directly or through activation of their receptors on adipocytes and in adipose tissues, facilitate adipose tissue deposition and function. Estrogens not only are protective in women, but a recent report by Finkelstein et al. further demonstrates that estrogens are necessary in men. Blocking conversion of androgens to estrogens resulted in reductions in insulin sensitivity and decrements in metabolism (Finkelstein et al., 2013). Evidence

References (72)

  • LissnerL. et al.

    Variation in energy intake during the menstrual cycle: implications for food-intake research

    Am. J. Clin. Nutr

    (1988)
  • LofM. et al.

    Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growth

    Am. J. Clin. Nutr

    (2005)
  • Martinez de MorentinP.B. et al.

    Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK

    Cell Metab

    (2014)
  • MessinaM.M. et al.

    Estradiol decreases the orexigenic effect of melanin-concentrating hormone in ovariectomized rats

    Physiol. Behav

    (2006)
  • RamirezM.E. et al.

    Evidence for sex steroid inhibition of lipoprotein lipase in men: comparison of abdominal and femoral adipose tissue

    Metabolism

    (1997)
  • RichelsenB. et al.

    Regional differences in triglyceride breakdown in human adipose tissue: effects of catecholamines, insulin, and prostaglandin E2

    Metabolism

    (1991)
  • SohlstromA. et al.

    Changes in adipose tissue volume and distribution during reproduction in Swedish women as assessed by magnetic resonance imaging

    Am. J. Clin. Nutr

    (1995)
  • TarttelinM.F. et al.

    Variations in food and water intake in the normal and acyclic female rat

    Physiol. Behav

    (1971)
  • WangT.J. et al.

    Impact of age and sex on plasma natriuretic peptide levels in healthy adults

    Am. J. Cardiol

    (2002)
  • XuY. et al.

    Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction

    Cell Metab

    (2011)
  • ZhuZ. et al.

    Central expression and anorectic effect of brain-derived neurotrophic factor are regulated by circulating estradiol levels

    Horm. Behav

    (2013)
  • AbildgarrdJ.P.A. et al.

    Menopause is associated with decreased whole body fat oxidation during exercise

    Am. J. Physiol. Endocrinol. Metab

    (2013)
  • AdlerE.S. et al.

    Neurochemical characterization and sexual dimorphism of projections from the brain to abdominal and subcutaneous white adipose tissue in the rat

    J. Neurosci

    (2012)
  • AsarianL. et al.

    Sex differences in the physiology of eating

    Am. J. Physiol. Regul. Integr. Comp. Physiol

    (2013)
  • BordicchiaM. et al.

    Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes

    J. Clin. Invest

    (2012)
  • BöhmC.1. et al.

    Sexual dimorphism in obesity-mediated left ventricular hypertrophy

    Am. J. Physiol. Heart Circ. Physiol

    (2013)
  • ClarkB.A. et al.

    The influence of gender, age, and the menstrual cycle on plasma atrial natriuretic peptide

    J. Clin. Endocrinol. Metab

    (1990)
  • CleggD.J. et al.

    Gonadal hormones determine sensitivity to central leptin and insulin

    Diabetes

    (2006)
  • CleggD.J. et al.

    Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats

    Diabetes

    (2007)
  • CollinsS.

    A heart-adipose tissue connection in the regulation of energy metabolism

    Nat. Rev. Endocrinol

    (2014)
  • CypessA.M. et al.

    Identification and importance of brown adipose tissue in adult humans

    N. Engl. J. Med

    (2009)
  • DavidsenL. et al.

    Impact of the menstrual cycle on determinants of energy balance: a putative role in weight loss attempts

    Int. J. Obes

    (2007)
  • EliasI. et al.

    Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance

    Diabetes

    (2012)
  • FinkelsteinJ.S. et al.

    Gonadal steroids and body composition, strength, and sexual function in men

    N. Engl. J. Med

    (2013)
  • FordE.S. et al.

    Trends in mean waist circumference and abdominal obesity among US adults, 1999–2012

    J. Am. Med. Assoc

    (2014)
  • GabrielyI. et al.

    Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?

    Diabetes

    (2002)
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