GPER Deficiency in Male Mice Results in Insulin Resistance, Dyslipidemia, and a Proinflammatory State

Abstract

Estrogen is an important regulator of metabolic syndrome, a collection of abnormalities including obesity, insulin resistance/glucose intolerance, hypertension, dyslipidemia, and inflammation, which together lead to increased risk of cardiovascular disease and diabetes. The role of the G protein-coupled estrogen receptor (GPER/GPR30), particularly in males, in these pathologies remains unclear. We therefore sought to determine whether loss of GPER contributes to aspects of metabolic syndrome in male mice. Although 6-month-old male and female GPER knockout (KO) mice displayed increased body weight compared with wild-type littermates, only female GPER KO mice exhibited glucose intolerance at this age. Weight gain in male GPER KO mice was associated with increases in both visceral and sc fat. GPER KO mice, however, exhibited no differences in food intake or locomotor activity. One-year-old male GPER KO mice displayed an abnormal lipid profile with higher cholesterol and triglyceride levels. Fasting blood glucose levels remained normal, whereas insulin levels were elevated. Although insulin resistance was evident in GPER KO male mice from 6 months onward, glucose intolerance was pronounced only at 18 months of age. Furthermore, by 2 years of age, a proinflammatory phenotype was evident, with increases in the proinflammatory and immunomodulatory cytokines IL-1β, IL-6, IL-12, TNFα, monocyte chemotactic protein-1, interferon γ-induced protein 10, and monokine induced by interferon gamma and a concomitant decrease in the adipose-specific cytokine adiponectin. In conclusion, our study demonstrates for the first time that in male mice, GPER regulates metabolic parameters associated with obesity and diabetes.

Selective activation of estrogen receptors, ERα and GPER-1, rapidly decreases food intake in female rats

“…Deletion of the GPER-1 gene in C57BL/6J mice produced an increase in visceral adiposity, relative to wildtype controls (Haas et al, 2009). A similar finding was reported by another group but food intake and locomotor activity were unaffected, suggesting that the obesity phenotype manifested via another mechanism (Sharma et al, 2013). A more recent study provided the first comprehensive examination of feeding behavior in GPER-1 null mice (Davis et al, 2014).…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Although roles for the classic ERs are well documented in these conditions (Faulds et al, 2012), GPER knockout mice also exhibit insulin resistance, glucose intolerance, dyslipidemia, obesity, and an elevation of proinflammatory cytokines with reduced adiponectin levels (Martensson et al, 2009;Sharma et al, 2013;Davis et al, 2014), despite displaying no differences in food intake or locomotor activity (Sharma et al, 2013;Davis et al, 2014). G-1, like E2, stimulates insulin secretion from the islets of mice (Sharma and Prossnitz, 2011) and humans (Kumar et al, 2011), with both G-1-and E2-mediated insulin secretion absent in islets of GPER knockout mice (Sharma and Prossnitz, 2011).…”

The G-protein coupled estrogen receptor, GPER: The inside and inside-out story

“…While clear roles for ERα and ERβ in these processes have been established from the use of knockout mice [Heine et al, 2000;Nilsson and Gustafsson, 2011]. GPER deficient mice also express dysregulated metabolic function [Martensson et al, 2009;Sharma et al, 2013], increased visceral adiposity , obesity [Haas et al, 2009; and altered bone development [Martensson et al, 2009;Ford et al, 2011].…”