G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis

Ewa Bielczyk-Maczynska (), Meng Zhao, Peter-James H. Zushin, Theresia M. Schnurr, Hyun-Jung Kim, Jiehan Li, Pratima Nallagatla, Panjamaporn Sangwung, Chong Y. Park, Cameron Cornn, Andreas Stahl, Katrin J. Svensson and Joshua W. Knowles ()
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Ewa Bielczyk-Maczynska: Stanford University School of Medicine
Meng Zhao: Stanford University School of Medicine
Peter-James H. Zushin: University of California at Berkeley
Theresia M. Schnurr: Stanford University School of Medicine
Hyun-Jung Kim: Stanford University School of Medicine
Jiehan Li: Stanford University School of Medicine
Pratima Nallagatla: Stanford University School of Medicine
Panjamaporn Sangwung: Stanford University School of Medicine
Chong Y. Park: Stanford University School of Medicine
Cameron Cornn: Stanford University School of Medicine
Andreas Stahl: University of California at Berkeley
Katrin J. Svensson: Stanford University School of Medicine
Joshua W. Knowles: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

Date: 2022
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DOI: 10.1038/s41467-022-35069-9

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