G protein-coupled estrogen receptor in energy homeostasis and obesity pathogenesis

Abstract

Obesity and its related metabolic diseases have reached a pandemic level worldwide. There are sex differences in the prevalence of obesity and its related metabolic diseases, with men being more vulnerable than women; however, the prevalence of these disorders increases dramatically in women after menopause, suggesting that sex steroid hormone estrogens play key protective roles against development of obesity and metabolic diseases. Estrogens are important regulators of several aspects of metabolism, including body weight and body fat, caloric intake and energy expenditure, and glucose and lipid metabolism in both males and females. Estrogens act in complex ways on their nuclear estrogen receptors (ERs) ERα and ERβ and transmembrane ERs such as G protein-coupled estrogen receptor. Genetic tools, such as different lines of knockout mouse models, and pharmacological agents, such as selective agonists and antagonists, are available to study function and signaling mechanisms of ERs. We provide an overview of the evidence for the physiological and cellular actions of ERs in estrogen-dependent processes in the context of energy homeostasis and body fat regulation and discuss its pathology that leads to obesity and related metabolic states.

Figure 6.1

Overview of estrogenic control of energy homeostasis, glucose, and lipid metabolism by regulatory actions in the CNS, adipose tissue, pancreatic β cells, skeletal muscles, and liver. Deficiency in estrogenic action leads to opposite events and subsequent disturbances in metabolic tissues. ERα, ERβ, and GPER play roles to regulate energy balance and glucose homeostasis. ERα and ERβ generally mediate opposing effects, while GPER generally has similar roles as ERα in the brain, adipose tissues, and pancreas.

Figure 6.2

Schematic overview of estradiol-mediated genomic signaling pathway via ERα/β and rapid nongenomic signaling pathways via GPER, Gq-mER, and membrane subpopulation mERα/β.