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') represent highly useful novel pharmacological tools. These designer receptors are unable to bind the endogenous muscarinic receptor agonist, acetylcholine. 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 involved in the regulation of food intake and energy expenditure. Metabolic studies with of some of these mutant mouse strains have 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 T2D and obesity (for a recent review, see for example: 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). 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 recent review, see: Pydi SP, Barella LF, Zhu L, Meister J, Rossi, Wess J. Annu Rev Physiol 84, 13.113.24, 2022. Adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis Chronically increased plasma FFA levels cause peripheral insulin resistance, a hallmark of T2D. We recently demonstrated that selective activation of adipocyte Gq signaling by a Gq-coupled designer receptor or by an agonist acting on an endogenous adipocyte Gq-coupled receptor (CysLT2 receptor) greatly improves glucose and lipid homeostasis in obese mice or in mice with adipocyte insulin receptor deficiency. These new findings indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis. (Kimura T, Pydi SP, Wang L, Haspula D, Cui Y, Lu H, Knig GM, Kostenis E, Steinberg GR, Gavrilova O, Wess J. Nat Commun 13(1):1652, doi: 10.1038/s41467-022-29231-6, 2022) Skeletal muscle beta-adrenergic receptor as potential targets for improving impaired glucose homeostasis Chronic treatment of WT mice with clenbuterol, a selective beta2-adrenergic receptor agonist, resulted in striking improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of T2D. We found that the beneficial metabolic effects of clenbuterol were mediated by activation of skeletal muscle (SKM) beta2-adrenergic receptors and the stimulatory G protein, Gs. Moreover, transcriptomic and metabolomic studies showed that chronic beta2-adrenergic receptor stimulation triggered metabolic reprogramming of SKM characterized by enhanced glucose utilization. These new data suggest are of significant translational relevance. (Meister J, Bone DBJ, Knudsen JR, Barella LF, Velenosi TJ, Akhmedov D, Lee RJ, Cohen AH, Gavrilova O, Cui Y, Karsenty G, Chen M, Weinstein LS, Kleinert M, Berdeaux R, Jensen TE, Richter EA, Wess J. Nat Commun 13(1):22, doi: 10.1038/s41467-021-27540-w, 2022) Metabolic consequences of acute activation of Gs-coupled receptors enriched in SKM By analyzing a series of mutant mouse models, we recently showed that acute activation of Gs signaling in SKM causes acute hyperglycemia. However, acute in vivo stimulation of endogenous Gs-coupled receptors enriched in SKM (beta2-adrenergic and CRF2 receptors) had 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. (Meister J, Bone DBJ, Knudsen JR, Barella LF, Liu L, Lee R, Gavrilova O, Chen M, Weinstein LS, Kleinert M, Jensen TE, Wess J. Mol Metab 55, 101415, 2022) Stimulation of cell Gq signaling causes multiple beneficial metabolic effects Improper regulation of glucagon release from cells plays a key role in the pathophysiology of both T1D and T2D. We recently used a chemogenetic strategy, we recently showed that acute stimulation of cell Gq signaling led to elevated plasma glucagon levels, accompanied by increased insulin release and improved glucose tolerance. Moreover, chronic activation of this pathway greatly improved glucose tolerance in obese mice. The Gq-coupled vasopressin 1b receptor (V1bR) is enriched in both mouse and human cells. Agonist-induced activation of the V1bR strongly stimulated glucagon release in a Gq-dependent fashion. In vivo studies indicated that V1bR-mediated glucagon release plays an important role in promoting glucagon secretion during hypoglycemia. These new findings implicate cell Gq signaling as an important regulator of glucagon secretion. (Liu L, Dattaroy D, Simpson KF, Barella LF, Cui Y, Xiong Y, Jin J, Knig GM, Kostenis E, Roman JC, Kaestner KH, Doliba NM, Wess J. JCI Insight 6(24):e152852, 2021) The following findings resulted from collaborative work with the labs of Dr. Kenneth Jacobson and Dr. Ann Dean at NIDDK: Deletion of hepatic adenosine A1 receptors in mice leads to multiple beneficial metabolic effects One of the key features of T2D is enhanced glucose production by the liver under fasting conditions. Hepatocytes express dozens of GPCRs including adenosine A1 receptors.To explore the potential metabolic relevance of hepatic A1 receptors, mutant mice lacking A1 receptors selectively in hepatocytes were generated and analyzed. These mutant mice showed a modest improvement in insulin sensitivity and decreased fasting blood glucose levels when mice consumed a high-fat diet. These data suggest that drugs able to inhibit hepatic A1 receptors may prove useful to lower pathologically elevated fasting blood glucose levels. (Jain S, Barella LF, Wess J, Reitman ML, Jacobson KA. Biochem Pharmacol 192:114739, 2021) Mice lacking the enhancer looping protein LDB1 in hepatocytes show pronounced metabolic phenotypes Recent work demonstrated that LDB1, a widely expressed protein that functions as an enhancer looping factor, regulates the expression of liver genes by occupying enhancer elements and cooperating with several hepatic transcription factors. Disruption of the Ldb1 gene in mouse hepatocytes resulted in dysregulation of metabolic gene expression and glucose intolerance. Surprisingly, Ldb1 knockout mice showed improved liver pathology when mice consumed a high fat diet, most likely due to enhanced expression of genes involved in liver fatty acid metabolism. More detailed studies are required to explore the possible translational relevance of these findings. (Liu G, Wang L, Wess J, Dean A. Nucleic Acids Res, in press)