The role of estrogens in control of energy balance and glucose homeostasis

Abstract

Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders.

Figure 1.

Origin of circulating and tissue estrogens. A, In healthy premenopausal women, estrogen (E2) is produced by the ovaries and functions as a circulating hormone that acts on distant target tissues. Here WAT is represented. B, In postmenopausal women and in men, E2 does not function as a circulating hormone; rather, it is synthesized in extragonadal sites from circulating androgenic precursors such as T, androstenedione (4A), or dehydroepiandrosterone (DHEA). Cellular estrogenic action depends on: 1) the ER signaling and sensitivity; 2) the activity of enzymes like aromatase involved in the biosynthesis of E2 from androgenic precursors; and 3) the inactivation of E2 in E2 sulfate (E2-S) by the estrogen sulfotransferase (EST).

Figure 2.

Summary of hypothalamic ERα actions regulating energy balance. In the hypothalamus, estrogen action through ERα in ARC POMC neurons suppresses food intake. On the other end, estrogen actions through ERα in VMN SF1 neurons stimulate physical activity and energy expenditure and regulate body fat distribution.

Figure 3.

Consequences of ERα deletion in skeletal muscle on metabolic dysfunction. Skeletal muscle-specific ERα deletion impairs muscle metabolism, leading to increased accumulation of bioactive lipids and muscle inflammation, which impairs muscle insulin action. Because skeletal muscle is a primary tissue responsible for fatty acid oxidation, impaired substrate oxidation promotes increased accumulation of fat in adipose tissue, which alters the secretory signature of the tissue inducing secondary phenotypes in muscle and liver. Thus, muscle ERα deletion precipitates impaired glucose tolerance and mild hepatic insulin resistance. The arrows represent the effect of skeletal muscle, adipose, and liver described above on each other.

Figure 4.

Summary of estrogen actions in glucose homeostasis and energy metabolism in physiology and menopause. Estrogen actions in the brain, adipose, pancreatic islets, skeletal muscle, liver, and macrophages synergize to promote glucose and lipid homeostasis. Estrogen deficiency or resistance in these tissues all contribute to metabolic dysfunction predisposing to the metabolic syndrome, type 2 diabetes, and obesity.