Role of GPRC6A in Regulating Hepatic Energy Metabolism in Mice

Min Pi,L Darryl Quarles,Fuyi Xu,Lu Lu,Robert W Williams,Satoru K Nishimoto,Ruisong Ye

doi:10.1038/s41598-020-64384-8

Min Pi, L Darryl Quarles + Show 5 more

Open Access

https://doi.org/10.1038/s41598-020-64384-8

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Abstract

GPRC6A is a widely expressed G-protein coupled receptor that regulates energy metabolism. Global deletion of Gprc6a in mice is reported to result in a metabolic syndrome-like phenotype and conditional deletion of Gprc6a in pancreatic β-cell and skeletal muscle respectively impair insulin secretion and glucose uptake. In the current study, we explore the hepatic functions of GPRC6A by conditionally deleting Gprc6a in hepatocytes by cross breeding Alb-Cre and Gprc6aflox/flox mice to obtain Gprc6aLiver-cko mice. Gprc6aLiver-cko mice on a normal diet showed excessive hepatic fat accumulation and glycogen depletion. These mice also exhibit impaired glucose and pyruvate tolerance, but normal insulin sensitivity. Decreased circulating FGF-21 levels and FGF-21 message expression in the liver were found in Gprc6aLiver-cko mice. Hepatic transcriptome analysis identified alterations in multiple pathways regulating glucose, fat and glycogen metabolism in Gprc6aLiver-cko mice. Taken together, our studies suggest that GPRC6A directly regulates hepatic metabolism as well as regulates the production and release of FGF-21 to control systemic energy homeostasis. GPRC6A’s unique regulation of β-cell, skeletal muscle and hepatic function may represent a new therapeutic target for treating disordered energy metabolism metabolic syndrome and type 2 diabetes.

Highlights

GPRC6A is a family C G-protein coupled receptor (GPCR) that consists of an N-terminal venus fly trap motif (VFTM) homologous to the bacterial periplasmic L-amino acid sensor fused with a classical 7 transmembrane domain (7-TM)
This study establishes an important role of GPRC6A in the liver to regulate glucose and fat metabolism
Loss-of-Gprc6a function in hepatocytes resulted in several metabolic abnormalities in Gprc6aLiver-cko mice, including hyperglycemia, reduced serum insulin levels, increased circulating concentrations of free fatty acids and cholesterol, impaired glucose and pyruvate tolerance tests, and increased fat and decreased glycogen content in the liver (Fig. 8)

Summary

Introduction

GPRC6A is a family C G-protein coupled receptor (GPCR) that consists of an N-terminal venus fly trap motif (VFTM) homologous to the bacterial periplasmic L-amino acid sensor fused with a classical 7 transmembrane domain (7-TM). This structure allows GPRC6A to sense multiple ligands, including the bone-derived peptide, osteocalcin (Ocn), amino acids, L-Arginine, L-Ornithine, and L-Lysine[1,2,3], testosterone (T)[1,4], and natural products in green tea[5]. The phenotype in the hepatocyte loss-of-function mouse model establishes a key role of GPRC6A in regulating hepatic glucose and fat metabolism in mice

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