G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis

Abstract

Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.

The Importance of G-protein Coupled Estrogen Receptor in Patients With Fibromyalgia

“…Pharmacological stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes. 28 In our study, GPER was not correlated with BMI in FMS patients. It was suggested that GPER has a modulator role in energy homeostasis (weight control).…”

The roles of estrogen and estrogen receptors in gastrointestinal disease (Review)

“…GPER1 activates multiple downstream signaling pathways, resulting in the activation of adenylate cyclase and increasing cyclic AMP levels, which promote intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate within the nucleus (16)(17)(18). GPER1 regulates a diverse range of biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function (19).…”

Estrogen withdrawal and replacement differentially target liver and adipose tissues in female mice fed a high-fat high-sucrose diet: impact of a chronic exposure to a low-dose pollutant mixture☆

“…All these beneficial effects progressively disappear with menopause. Estrogens act through specific receptors distributed centrally and peripherally including ERα, ERβ and the G-protein-coupled receptor GPR30 which differ in abundance and tissue distribution in a sex-dependent manner [16,19,20]. Non-genomic actions of estrogens as well as cross-talk with various nuclear receptors and/or transcription factors have also been evidenced [21,22].…”