Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors

Abstract

Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men.

Figure 1

Factors contributing to the development of obesity and its metabolic and cardiovascular consequences. Predominant causes are excessive calorie intake combined with physical inactivity. This has resulted in an alarming, world-wide increase in the prevalence of obesity. Adapted from (Barton et al., 2003).

Figure 2

Proposed role of ERα, ERβ, and GPER for the regulation of body weight and maintenance of glucose homeostasis. In premenopausal women, 17β-estradiol (E₂) is the predominant estrogen released by the ovaries. The main source of estrogen in men and postmenopausal women is adipose tissue, where E₂ is converted from androgen precursors by the aromatase enzyme. E₂ has paracrine effects on adipocytes, but also acts centrally in the brain, as well as peripherally in organs regulating glucose homeostasis, such as the endocrine pancreas, liver, and skeletal muscle. Note that ERα and ERβ generally mediate opposing effects, whereas the role of GPER has only been in part investigated. In addition, insulin released by pancreatic β-cells regulates hepatic glucose production via gluconeogensis and glucose uptake in skeletal muscle, which is impaired by the action of inflammatory mediators released by adipose tissue. +, stimulatory effect; −, inhibitory effect; ?, effect unknown.