Journal Article

GPRC6A Null Mice Exhibit Osteopenia, Feminization and Metabolic Syndrome

Li, Benyi, Quarles, L. Darryl, Faber, Pieter, Luo, Junming, Ringhofer, Brian, Harrington, John J., Zhu, Wenyu, Zhang, Jianghong, Huang, Min-Zhao, Jackson, P. David, Pi, Min, Chen, Ling, Christenson, Lane, Brunden, Kurt R.

2008

Overview

GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown. In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone. GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 17β-Estradiol / Abnormalities / Amino acids / Animal tissues / Animals / Biocompatibility / Biomedical materials / Blotting, Western / Body fat / Body mass / Bone and Bones - metabolism / Bone density / Bone Density - genetics / Bone Diseases, Metabolic - genetics / Bone mineral density / Calcium / Cations / Cell Biology / Diabetes and Endocrinology/Bone and Mineral Metabolism / Diabetes and Endocrinology/Obesity / Diabetes and Endocrinology/Reproductive Endocrinology / Distal tubules / Divalent cations / Estradiol / Exhibitions / Fatty liver / Fatty Liver - genetics / Female / Feminization / Feminization - genetics / G protein-coupled receptors / Gastroenterology and Hepatology/Hepatology / Gene Deletion / Gene Expression / Genotype & phenotype / Glucose / Glucose tolerance / Gonadal Steroid Hormones - blood / Hyperglycemia / Insulin / Insulin - metabolism / Insulin resistance / Intolerance / Kidney - abnormalities / Kidney - physiopathology / Kidneys / Lean body mass / Leydig cells / Liver / Liver diseases / Low molecular weights / Male / Metabolic disorders / Metabolic syndrome / Metabolic Syndrome - genetics / Metabolism / Mice / Mice, Knockout - abnormalities / Mineralization / Molecular weight / Musculoskeletal Abnormalities / Nephrology/Mineral Metabolism and the Kidney / Osteoporosis / Phenotype / Phenotypes / Phosphorus / Physiological aspects / Physiology / Physiology/Endocrinology / Proteins / Proteinuria / Proximal tubules / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - physiology / Renal function / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Scholarships & fellowships / Sex hormones / Testes / Testosterone / Transcription factors / Urine