GPR30-mediated activation of STAT3-anorexigenic pathway by estrogen in the hypothalamus

Abstract

Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, it is unknown which type of estrogen receptor mediates this regulation. In this study, the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus was investigated. E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. E2-induced pSTAT3 activation was inhibited by EGFR inhibitor or pertussis toxin. G-1, a specific agonist of GPR30, induced pSTAT3 and G-15, a specific antagonist of GPR30, inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. Intracerebroventricular (ICV) injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. These pSTAT3 signals were colocalized with POMC neurons in the arcuate nucleus. ICV injection of G-15 inhibited G-1-induced pSTAT3 activation and E2-induced decrease in food intake and body weight gain. These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus, which may provide a basis for future therapeutic interventions of obesity.