Role of G protein-coupled receptors in regulating glucose and energy homeostasis

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

SUMMARY Use of designer GPCRs to study GPCR regulation of key metabolic pathways Muscarinic receptor-based designer GPCRs referred to as DREADDs ('designer receptors exclusively activated by designer drugs') have emerged as highly useful novel pharmacological tools. These designer receptors are unable to bind the endogenous muscarinic receptor agonist, acetylcholine, due to two single point mutations introduced into the transmembrane receptor core. Importantly, DREADDs can be efficiently activated by certain clozapine derivatives (CNO, DCZ, etc.) which are otherwise pharmacologically inert. We are currently in the process of expressing DREADDs with different G protein coupling properties (Gq, Gs, Gi, or G12) in various metabolically relevant cell types. These cell types include adipocytes, pancreatic beta- and alpha-cells, skeletal muscle cells, hepatocytes, and certain neuronal subpopulations of the hypothalamus. Metabolic analysis of these mutant mouse strains has identified several novel pathways that are critical for maintaining blood glucose and energy homeostasis. The new insights gained from this work should inform the development of novel classes of drugs useful for the treatment of several metabolic disorders including type 2 diabetes and obesity. We recently reviewed the power of DREADD technology: Kang H-J, Minamoto T, Wess J, Roth BL. Chemogenetics for cell-type specific modulation of signaling and neuronal activity. Nat Rev Meth Primers 3, 93, 2023. Stimulation of G12/13 signaling in POMC neurons modulates key metabolic functions Pro-opiomelanocortin (POMC)-containing neurons are located in the accurate nucleus (ARC) of the hypothalamus where they play a key role in maintaining glucose and energy homeostasis. Like essentially all other cell types, POMC neurons express dozens of distinct GPCRs. Several studies have explored the functional outcomes of activating Gs-, Gi-, or Gq-coupled GPCRs in distinct neuronal populations of the ARC. Although G proteins of the G12 family (G12 and G13) are widely expressed throughout the brain , the physiological or pathophysiological roles of neuronal G12/13 signaling remain largely unknown. Published transcriptomics data indicate that mouse ARC POMC neurons express relatively high levels of several receptors that can couple to G12/13, in addition to other functional classes of G proteins. Based on these findings, we explored the potential metabolic roles of G12-type G proteins expressed by POMC neurons in regulating glucose and energy homeostasis. Detailed metabolic studies with several newly generated mouse models resulted in a several important novel findings. Chemogenetic activation of G12/13 signaling in POMC neurons led to pronounced improvements in glucose homeostasis due to various mechanisms including changes in autonomic outflow. Studies with G12/13 knockout mice showed that G12/13 signaling in POMC neurons mediates the beneficial metabolic effects of lorcaserin, an appetite-suppressant drug that selectively activates serotonin 5-HT2C receptors. These new findings provide a rational basis for the development of new classes of drugs aimed at enhancing G12/13 signaling in POMC neurons for the treatment of various metabolic disorders including obesity and type 2 diabetes. Activation of Gs signaling in enteroendocrine K-cells causes multiple beneficial metabolic effects Glucose-dependent insulinotropic polypeptide (GIP) is the most important incretin hormone required for maintaining euglycemia in healthy humans. GIP, together with GLP-1, another major incretin hormone, is released from specialized enteroendocrine cells after a meal. The activation of GIP and GLP-1 receptors expressed by pancreatic beta-cells promotes insulin secretion, thus rapidly lowering elevated blood glucose levels. To explore the potential role of K-cell Gs signaling in GIP release and whole body glucose homeostasis, we generated a novel mouse model that allowed us to selectively stimulate K-cell Gs signaling. In addition, we generated a mouse strain lacking Galpha-s selectively in K-cells. Metabolic phenotyping studies indicated that strategies aimed at enhancing K-cell Gs signaling may prove useful for the treatment of diabetes and related metabolic diseases. G12/13 signaling in hepatocytes enhances blood glucose levels Like most other cell types, hepatocytes express many GPCRs which are linked to different functional classes of heterotrimeric G proteins. GPCR/G protein-stimulated signaling pathways represent important regulators of hepatic glucose fluxes. Although many GPCRs can couple to G proteins of the G12 family (G12/13), the metabolic roles of G12/13 have not been studied systematically in the past. To explore the potential role of G12/13 signaling in regulating hepatic physiology, we generated and analyzed several novel gain- and loss-of-function mutant mouse models. We found that selective activation of hepatocyte G12/13 signaling leads to pronounced increases in blood glucose levels and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. The physiological and pathophysiological implications of this new finding is currently the focus of intense investigation. REFERENCES Haspula D, Cui Z, Pittala S, Cui Y, Lu H, Xiong Y, Jin J, Gavrilova O, Hwang E, Ajwani J, Portillo B, Williams KW, Inoue A, Wess J. G proteins of the G12 family expressed by POMC neurons regulate key metabolic functions. Sci Advances 11(28):eadu1670, 2025. Pittala S, Haspula D, Cui Y, Yang WM, Kim YB, Davis RJ, Wing A, Rotman Y, McGuinness OP, Inoue A, Wess J. G12/13-mediated signaling stimulates hepatic glucose production and has a major impact on whole body glucose homeostasis. Nature Commun 15(1):9996. doi: 10.1038/s41467-024-54299-7, 2024. Oteng AB, Liu L, Cui Y, Gavrilova O, Lu H, Chen M, Weinstein LS, Campbell JE, Lewis JE, Gribble FM, Reimann F, Wess J. Activation of Gs signaling in mouse enteroendocrine K-cells greatly improves obesity- and diabetes-related metabolic deficits. J Clin Invest 134:e182325, 2024.