Selective activation of G(s) signaling in adipocytes causes striking metabolic improvements in mice

OBJECTIVE: Given the worldwide epidemics of obesity and type 2 diabetes, novel antidiabetic and appetite-suppressing drugs are urgently needed. Adipocytes play a central role in the regulation of whole-body glucose and energy homeostasis. The goal of this study was to examine the metabolic effects of acute and chronic activation of G(s) signaling selectively in adipocytes (activated G(s) stimulates cAMP production), both in lean and obese mice. METHODS: To address this question, we generated a novel mutant mouse strain (adipo-GsD mice) that expressed a G(s)-coupled designer G protein-coupled receptor (Gs DREADD or short GsD) selectively in adipocytes. Importantly, the GsD receptor can only be activated by administration of an exogenous agent (CNO) that is otherwise pharmacologically inert. The adipo-GsD mice were maintained on either regular chow or a high-fat diet and then subjected to a comprehensive series of metabolic tests. RESULTS: Pharmacological (CNO) activation of the GsD receptor in adipocytes of adipo-GsD mice caused profound improvements in glucose homeostasis and protected mice against the metabolic deficits associated with the consumption of a calorie-rich diet. Moreover, chronic activation of G(s) signaling in adipocytes led to a striking increase in energy expenditure and reduced food intake, resulting in a decrease in body weight and fat mass when mice consumed a calorie-rich diet. CONCLUSION: Systematic studies with a newly developed mouse model enabled us to assess the metabolic consequences caused by acute or chronic activation of G(s) signaling selectively in adipocytes. Most strikingly, chronic activation of this pathway led to reduced body fat mass and restored normal glucose homeostasis in obese mice. These findings are of considerable relevance for the development of novel antidiabetic and anti-obesity drugs.