Role of estrogen in the regulation of central and peripheral energy homeostasis: from a menopausal perspective

Abstract

Estrogen plays a prominent role in regulating and coordinating energy homeostasis throughout the growth, development, reproduction, and aging of women. Estrogen receptors (ERs) are widely expressed in the brain and nearly all tissues of the body. Within the brain, central estrogen via ER regulates appetite and energy expenditure and maintains cell glucose metabolism, including glucose transport, aerobic glycolysis, and mitochondrial function. In the whole body, estrogen has shown beneficial effects on weight control, fat distribution, glucose and insulin resistance, and adipokine secretion. As demonstrated by multiple in vitro and in vivo studies, menopause-related decline of circulating estrogen may induce the disturbance of metabolic signals and a significant decrease in bioenergetics, which could trigger an increased incidence of late-onset Alzheimer's disease, type 2 diabetes mellitus, hypertension, and cardiovascular diseases in postmenopausal women. In this article, we have systematically reviewed the role of estrogen and ERs in body composition and lipid/glucose profile variation occurring with menopause, which may provide a better insight into the efficacy of hormone therapy in maintaining energy metabolic homeostasis and hold a clue for development of novel therapeutic approaches for target tissue diseases.

Keywords: energy homeostasis; estrogen; glucose; lipid; menopause; obesity.

Figure 1.

Schematic representation of biosynthesis of estradiol (E2), estriol (E3), and estrone (E1). E2, with the highest affinity to ERs, is primarily secreted by ovarian granulosa cells in premenopausal women. E1 and E3 are the metabolites of E2, both of which are much less potent than E2. Besides, E1 is the main estrogen after menopause synthesized in peripheral adipose and skin tissue, while E3 is mainly produced by the placenta in pregnant women.

Figure 2.

Overview of intracellular 17β-estradiol (E2) signaling. E2 signaling is mediated by ERs, which include two typical isoforms, ERα and ERβ. (a) Genomic signaling involves two different models occurring within hours. E2-activated dimerized ERs directly bind to nuclear ERE on the promotor of target protein regulating transcriptional responses, or modulating specific transcription factors or activator protein 1 indirectly regulating transcriptional responses. (b) Nongenomic ERs rapid signaling occurs within minutes or seconds across the plasma membrane. Member-embedded ERs or G protein-coupled ER (GPR30) are initiated by E2 and subsequently activate multiple signaling pathways, such as Src, MAPK, and AKT signaling cascades, to induce downstream ion fluxes and protein kinases activation. Mitochondria is also the target organelle of E2, where both ERα and ERβ are localized for maintaining cellular bioenergetics. Mitochondrial DNA contains ERE-like sequences, which is activated by E2-ER to regulate mitochondrial function. ER, estrogen receptor; ERE, estrogen response element.

Figure 3.

Model of 17β-estradiol (E2)’s homeostatic regulation of energy balance in the brain. Brain regulation of energy homeostasis is mainly reliant on hypothalamic and brainstem-associated neuronal populations, including those in the arcuate nucleus (ARC), lateral hypothalamus (LH), ventromedial nucleus (VMN), dorsomedial nucleus, and the paraventricular nucleus, which are modulated by E2 signaling, and deliver orexigenic or anorexigenic signals to stimulate or suppress the energy intake and the energy expenditure. Proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons and neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in ARC may regulate the body energy status through POMC/α-melanocortin stimulating hormone signaling. POMC neurons are impinged by steroidogenic factor-1 neurons in the VMN, while NPY/AgRP neurons project to melanin-concentrating hormone neurons in LH. Nucleus tractus solitarius in the brainstem, which receives abdominal vagal afferent projections activated by the peptide cholecystokinin, may modulate the feeding inhibition effect via E2 signaling.