Objective The goal of this study was to determine the glucometabolic effects of acute activation of G s signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis. Methods To address this question, we studied mice that express a G s -coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two G s -coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β 2 -adrenergic receptor and CRF 2 receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively). Results Acute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β 2 -adrenergic and, potentially, CRF 2 receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM G s signaling. Conclusions Selective activation of G s signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous G s -coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release.

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The functional state of adipocytes plays a central role in regulating numerous important metabolic functions, including energy and glucose homeostasis. While white adipocytes store excess calories as fat (triglycerides) and release free fatty acids as a fuel source in times of need, brown and beige adipocytes (so-called thermogenic adipocytes) convert chemical energy stored in substrates (e.g., fatty acids or glucose) into heat, thus promoting energy expenditure. Like all other cell types, adipocytes express many G protein–coupled receptors (GPCRs) that are linked to four major functional classes of heterotrimeric G proteins (Gs, Gi/o, Gq/11, and G12/13). During the past few years, novel experimental approaches, including the use of chemogenetic strategies, have led to a series of important new findings regarding the metabolic consequences of activating or inhibiting distinct GPCR/G protein signaling pathways in white, brown, and beige adipocytes. This novel information should guide the development of novel drugs capable of modulating the activity of specific adipocyte GPCR signaling pathways for the treatment of obesity, type 2 diabetes, and related metabolic disorders.