Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity

Abstract

Because of increasing life expectancy, the contribution of age-related estrogen or androgen deficiency to obesity and type 2 diabetes will become a new therapeutic challenge. This review integrates current concepts on the mechanisms through which estrogen receptors (ERs) and androgen receptor (AR) regulate energy homeostasis in rodents and humans. In females, estrogen maintains energy homeostasis via ERα and ERβ, by suppressing energy intake and lipogenesis, enhancing energy expenditure, and ameliorating insulin secretion and sensitivity. In males, testosterone is converted to estrogen and maintains fuel homeostasis via ERs and AR, which share related functions to suppress adipose tissue accumulation and improve insulin sensitivity. We suggest that ERs and AR could be potential targets in the prevention of age-related metabolic disorders.

Figure 1. Metabolic effects of ERα and ERβ activation in females

Activation of ERα in the central nervous system (CNS) suppresses food intake, increases energy expenditure and decreases body weight. In addition, activation of ERα improves peripheral energy and glucose homeostasis in multiple ways by 1) preventing liver steatosis, suppressing hepatic glucose production and improving insulin sensitivity, 2) enhancing skeletal muscle lipid oxidation, GLUT4 expression and insulin sensitivity, 3) enhancing subcutaneous white adipose tissue (WAT) distribution while decreasing overall WAT mass by decreasing WAT free fatty acid (FFA) uptake, lipid synthesis and increasing lipolysis, 4) favoring pancreatic β-cell survival and function by preventing pro-apoptotic injuries and lipotoxicity, and increasing insulin biosynthesis and glucose-stimulated insulin release (GSIS). Activation of ERβ in the central nervous system (CNS) also suppresses food intake and increases energy expenditure and prevents obesity on a high fat diet. In addition, activation of ERβ affects peripheral energy and glucose homeostasis by 1) favoring pancreatic β-cell survival and function by preventing pro-apoptotic injuries and increasing GSIS, 2) preventing obesity and decreasing WAT mass, 3) promoting insulin resistance in absence of ERα activation. ERα and ERβ metabolic actions on peripheral tissues result from direct activations of ERs in these tissues or from a central ER action affecting peripheral tissues via the autonomous system CNS ERs.

Figure 2. Metabolic effects of ERα and ERβ activation in males

Activation of ERα in males has similar effect than in females. In the central nervous system (CNS), ERα suppresses food intake, increases energy expenditure and decreases body weight. In addition, activation of ERα improves peripheral energy and glucose homeostasis in multiple ways by 1) preventing liver steatosis, suppressing hepatic glucose production and improving insulin sensitivity, 2) enhancing skeletal muscle lipid oxidation, GLUT4 expression and insulin sensitivity, 3) enhancing subcutaneous white adipose tissue (WAT) distribution while decreasing overall WAT mass by decreasing WAT free fatty acid (FFA) uptake, lipid synthesis and increasing lipolysis, 4) favoring pancreatic β-cell survival and function by preventing pro-apoptotic injuries and lipotoxicity, and increasing insulin biosynthesis and glucose-stimulated insulin release (GSIS). Activation of ERβ in the central nervous system (CNS) also suppresses food intake and increases energy expenditure and prevents obesity on a high fat diet. In addition, activation of ERβ affects peripheral energy and glucose homeostasis by 1) favoring pancreatic β-cell survival and function by preventing pro-apoptotic injuries and increasing GSIS, 2) preventing obesity and decreasing WAT mass, 3) promoting insulin resistance in absence of ERα activation. ERα and ERβ metabolic actions on peripheral tissues result from direct activations of ERs in these tissues or from a central ER action affecting peripheral tissues via the autonomous system CNS ERs.

Figure 3. Metabolic effects of AR activation in males

Physiological activation of AR in the central nervous system (CNS) suppresses food intake, increases energy expenditure and decreases body weight. In addition, physiological activation of AR improves peripheral energy and glucose homeostasis by 1) preventing liver steatosis 2) enhancing skeletal muscle insulin sensitivity by increasing PGC1α expression, mitochondrial biogenesis and skeletal muscle oxidative fibers, thus increasing lipid oxidation, 3) decreasing WAT lipogenesis and visceral WAT mass. AR activation also decreases WAT adiponectin and leptin production.