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

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 a compound called clozapine-N-oxide (CNO), an agent that is 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 key findings obtained with mice expressing different DREADDs in adipose tissue: REF: Liu L, Wess J. Adipocyte G protein-coupled receptors as potential targets for novel antidiabetic drugs. Diabetes 72, 825-834, 2023. Key metabolic roles of beta-arrestin-1 and 2 studied with cell-type specific mutant mice To explore the potential metabolic roles of the two beta-arrestins in modulating glucose and energy homeostasis, we are analyzing mutant mice that lack or over-express beta-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic studies showed that both beta-arrestins play key roles in regulating several important metabolic functions, including whole-body glucose and/or energy homeostasis. Mouse phenotyping studies also revealed that beta-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various severe disorders of glucose and energy homeostasis. For a comprehensive recent review, see: REF: Wess J, Oteng A-B, Rivera-Gonzalez O, Gurevich EV, and Gurevich VV. -Arrestins: structure, function, physiology, and pharmacological perspectives. Pharmacol Rev, doi: 10.1124/pharmrev.121.000302. Online ahead of print, April 2023. Outcome of a collaborative study with the lab of Dr. Ann Dean at NIDDK LDB1 regulates hepatic gene expression and is required for proper glucose homeostasis The liver plays a central role in the regulation of blood glucose levels. We recently showed that the Lim domain binding protein 1 (LDB1), an enhancer looping protein, regulates the expression of several metabolically important liver genes including Slc2a2 which codes for GLUT2, the principal glucose transporter expressed by hepatocytes. Interestingly, deletion of Ldb1 in adult mouse liver resulted in glucose intolerance, suggesting that hepatic LDB1 is essential for maintaining proper glucose homeostasis. REF: Guoyou Liu G, Wang L, Wess J, Dean A. Enhancer looping protein LDB1 regulates hepatocyte gene expression by cooperating with liver transcription factors. Nucleic Acids Res 50, 9195-9211, 2022