GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome

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

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Background: 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. Methods/Principal Findings: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 PO4/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. Conclusions/Significance: 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.

Original languageEnglish (US)
Article numbere3858
JournalPLoS One
Volume3
Issue number12
DOIs
StatePublished - Dec 3 2008
Externally publishedYes

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Feminization
osteopenia
feminization
Metabolic Bone Diseases
metabolic syndrome
Bone
Osteocalcin
Divalent Cations
mice
Liver
Physiologic Calcification
bone mineralization
osteocalcin
Glucose Intolerance
Amino Acids
Glucose
fatty liver
kidneys
Osteoblasts
G-Protein-Coupled Receptors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. / Pi, Min; Chen, Ling; Huang, Min Zhao; Zhu, Wenyu; Ringhofer, Brian; Luo, Junming; Christenson, Lane; Li, Benyi; Zhang, Jianghong; Jackson, P. David; Faber, Pieter; Brunden, Kurt R.; Harrington, John J.; Quarles, Leigh.

In: PLoS One, Vol. 3, No. 12, e3858, 03.12.2008.

Research output: Contribution to journalArticle

Pi, M, Chen, L, Huang, MZ, Zhu, W, Ringhofer, B, Luo, J, Christenson, L, Li, B, Zhang, J, Jackson, PD, Faber, P, Brunden, KR, Harrington, JJ & Quarles, L 2008, 'GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome', PLoS One, vol. 3, no. 12, e3858. https://doi.org/10.1371/journal.pone.0003858
Pi, Min ; Chen, Ling ; Huang, Min Zhao ; Zhu, Wenyu ; Ringhofer, Brian ; Luo, Junming ; Christenson, Lane ; Li, Benyi ; Zhang, Jianghong ; Jackson, P. David ; Faber, Pieter ; Brunden, Kurt R. ; Harrington, John J. ; Quarles, Leigh. / GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. In: PLoS One. 2008 ; Vol. 3, No. 12.
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abstract = "Background: 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. Methods/Principal Findings: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 PO4/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. Conclusions/Significance: 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.",
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AU - Pi, Min

AU - Chen, Ling

AU - Huang, Min Zhao

AU - Zhu, Wenyu

AU - Ringhofer, Brian

AU - Luo, Junming

AU - Christenson, Lane

AU - Li, Benyi

AU - Zhang, Jianghong

AU - Jackson, P. David

AU - Faber, Pieter

AU - Brunden, Kurt R.

AU - Harrington, John J.

AU - Quarles, Leigh

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AB - Background: 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. Methods/Principal Findings: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 PO4/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. Conclusions/Significance: 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.

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