Abstract
We show that GPRC6A, an osteocalcin-sensing G-protein coupled receptor GPRC6A, uniquely regulates glucose and fatty acid metabolism in the liver. Conditional deletion of GPRC6A in hepatocytes results in hepatic fat accumulation and glycogen depletion associated with impaired glucose and pyruvate tolerance and suppression of FGF-21 in mice. Conversely, knock-in of a human KGKY gain-of-function polymorphism in the 3rd intracellular loop of GPRC6A, in mice results in reduced blood glucose associated with improved glucose, insulin and pyruvate tolerance and increased FGF-21. Hepatic transcriptome analysis shows that GPRC6A has counter regulatory effects on fatty acid oxidation and synthesis and glycolysis and gluconeogenesis, and concordant effects on glycogenesis and glycogenolysis. Taken together, our studies suggest that the level of GPRC6A activation determines how glucose and FAs are utilized by the liver. GPRC6A may be a new therapeutic target for treating metabolic syndrome and its complications.
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