Abstract
ObjectiveGiven 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 Gs signaling selectively in adipocytes (activated Gs stimulates cAMP production), both in lean and obese mice. MethodsTo address this question, we generated a novel mutant mouse strain (adipo-GsD mice) that expressed a Gs-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. ResultsPharmacological (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 Gs 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. ConclusionSystematic studies with a newly developed mouse model enabled us to assess the metabolic consequences caused by acute or chronic activation of Gs 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.
Highlights
Type 2 diabetes (T2D) has emerged as a major health problem in most parts of the world
Pharmacological (CNO) activation of the Gscoupled DREADD (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
Systematic studies with a newly developed mouse model enabled us to assess the metabolic consequences caused by acute or chronic activation of Gs signaling selectively in adipocytes. Chronic activation of this pathway led to reduced body fat mass and restored normal glucose homeostasis in obese mice
Summary
Type 2 diabetes (T2D) has emerged as a major health problem in most parts of the world. Little is known about how activation of these various GPCR/G protein pathways affects glucose homeostasis under physiological and pathophysiological conditions in vivo. Studies in this field have been hampered by the lack of GPCR subtype-selective ligands and the fact that the GPCRs expressed by adipocytes are present in many other tissues. To circumvent these difficulties, we started to employ a novel experimental strategy that involves the use of designer GPCRs that can only be activated by an exogenously administered drug [8,9]. Most DREADDs are mutant muscarinic acetylcholine receptors that no longer
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