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 some 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 these studies comprehensively: Wang L, Zhu L, Meister J, Bone DB, Pydi SP, Rossi, Wess J. Use of DREADD technology to identify novel targets for anti-diabetic drugs. Annu Rev Pharmacol Toxicol 61, 421-440, 2021. Meister J, Wang L, Pydi SP, Wess J. Chemogenetic approaches to identify metabolically important GPCR signaling pathways: Therapeutic implications. J Neurochem 32, 112-129, 2021. Key metabolic roles of beta-arrestin-1 and 2 studied with cell-type specific mutant mice To study the potential metabolic roles of the two beta-arrestins in modulating glucose and energy homeostasis, we recently analyzed mutant mice that lacked or over-expressed beta-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both beta-arrestins play key roles in regulating several important metabolic functions, resulting in striking changes in whole-body glucose and/or energy homeostasis. These 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. We recently reviewed this work in a comprehensive fashion: Pydi SP, Barella LF, Meister J, Wess J. Key metabolic functions of -arrestins: Studies with novel mouse models. Trends Endocrinol Metab 32, 118-129, 2021. Pydi SP, Barella LF, Zhu L, Meister J, Rossi, Wess J. Beta-arrestins as important regulators of glucose and energy homeostasis. Annu Rev Physiol, in press. Beta-arrestin-1 plays a key role in regulating beta-cell proliferation Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. We recently found that beta-arrestin-1 (barr1) is essential for beta-cell replication and function in insulin-resistant mice maintained on a high fat diet that causes obesity. Specifically, insulin-resistant beta-cell-specific barr1 knockout mice displayed striking reductions in beta-cell mass and the rate of beta-cell proliferation, associated with pronounced impairments in glucose homeostasis. Additonal studies indicated that the observed metabolic deficits resulted from reduced Pdx1 expression levels caused by beta-cell barr1 deficiency. These novel findings suggest that strategies aimed at enhancing barr1 activity and/or expression in beta-cells may stimulate the development of novel classes of antidiabetic drugs. (Barella LF, Rossi M, Pydi SP, Meister J, Jain S, Cui Y, Gavrilova O, Fulgenzi G, Tessarollo L, Wess J. Beta-arrestin-1 is required for adaptive beta-cell mass expansion during obesity. Nat Commun 12, 3385, doi.org/10.1038/s41467-021-23656-1, 2021) The following findings resulted from a collaboration with the lab of Dr. Kenneth Jacobson at NIDDK: Adipocyte P2Y14 receptors mediate important metabolic functions Drugs that are able to regulate adipocyte function are predicted to have considerable therapeutic potential. Interestingly, metabolic studies withe adipocyte-specific P2Y14 receptor mutant mice showed that the lack of this receptor subtype in adipocytes caused enhanced lipolysis, decreased body weight, and improved glucose tolerance and insulin sensitivity. Additional in vitro and in vivo data supported the concept that adipose tissue P2Y14 receptors are critical regulators of whole-body glucose and lipid homeostasis, suggesting that P2Y14 receptor antagonists may prove useful for the therapy of obesity and T2D. (Jain S, Pydi SP, Jung YH, Scortichini M, Kesner EL, Karcz TP, Cook DN, Gavrilova O, Wess J, Jacobson KA. Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and lipid homeostasis. JCI Insight 6, 146577, 2021) Key metabolic role of adipocyte P2Y6 receptors The purinergic P2Y6 receptor (endogenous ligand: UDP) is known to regulate various important metabolic functions. We recently found that adipocyte-specific deletion of this receptor subtype protects mice from diet-induced obesity, thus improving glucose tolerance and insulin sensitivity. Interestingly, whole body P2Y6 receptor knockout mice showed metabolic improvements similar to those observed with adipocyte-specific P2Y6 receptor knockout mice. These new findings indicate that P2Y6 receptor antagonists may prove beneficial for the treatment of disorders of glucose and energy homeostasis. (Jain S, Pydi SP, Toti KS, Robaye B, Idzko M, Gavrilova O, Wess J, Jacobson KA. Lack of adipocyte purinergic P2Y6 receptor greatly improves whole body glucose homeostasis. Proc Natl Acad Sci USA 117, 30763-30774, 2020)