A novel experimental strategy to assess the metabolic effects of selective activation of a G(q)-coupled receptor in hepatocytes in vivo.

Li JH, Jain S, McMillin SM, Cui Y, Gautam D, Sakamoto W, Lu H, Jou W, McGuinness OP, Gavrilova O, Wess J
Endocrinology. 2013 154 (10): 3539-51

PMID: 23861369 · PMCID: PMC3776870 · DOI:10.1210/en.2012-2127

Increased hepatic glucose production is a key pathophysiological feature of type 2 diabetes. Like all other cell types, hepatocytes express many G protein-coupled receptors (GPCRs) that are linked to different functional classes of heterotrimeric G proteins. The important physiological functions mediated by G(s)-coupled hepatic glucagon receptors are well-documented. In contrast, little is known about the in vivo physiological roles of hepatocyte GPCRs that are linked to G proteins of the G(q) family. To address this issue, we established a transgenic mouse line (Hep-Rq mice) that expressed a G(q)-linked designer receptor (Rq) in a hepatocyte-selective fashion. Importantly, Rq could no longer bind endogenous ligands but could be selectively activated by a synthetic drug, clozapine-N-oxide. Clozapine-N-oxide treatment of Hep-Rq mice enabled us to determine the metabolic consequences caused by selective activation of a G(q)-coupled GPCR in hepatocytes in vivo. We found that acute Rq activation in vivo led to pronounced increases in blood glucose levels, resulting from increased rates of glycogen breakdown and gluconeogenesis. We also demonstrated that the expression of the V(1b) vasopressin receptor, a G(q)-coupled receptor expressed by hepatocytes, was drastically increased in livers of ob/ob mice, a mouse model of diabetes. Strikingly, treatment of ob/ob mice with a selective V(1b) receptor antagonist led to reduced glucose excursions in a pyruvate challenge test. Taken together, these findings underscore the importance of G(q)-coupled receptors in regulating hepatic glucose fluxes and suggest novel receptor targets for the treatment of type 2 diabetes.

MeSH Terms (23)

Animals Antidiuretic Hormone Receptor Antagonists Cells, Cultured Diabetes Mellitus, Type 2 Enzyme Activators Female G-Protein-Coupled Receptor Kinases Gluconeogenesis Glycogenolysis GTP-Binding Protein alpha Subunits, Gq-G11 Hepatocytes Humans Hypoglycemic Agents Male Mice Mice, Obese Mice, Transgenic Protein Engineering Protein Interaction Domains and Motifs Receptor, Muscarinic M3 Receptors, Vasopressin Recombinant Fusion Proteins Specific Pathogen-Free Organisms

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