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GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome
Min Pi1, Ling Chen, Min-Zhao Huang
1The Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
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 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.
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.
Insights
The GPRC6A receptor plays a key role in coordinating metabolic responses. Its absence in mice leads to a metabolic syndrome affecting bone, kidney, liver, and testes.
Area of Science:
- Endocrinology
- Metabolic Syndrome Research
- G-protein coupled receptor signaling
Background:
- GPRC6A is an orphan G-protein coupled receptor with known sensing capabilities for amino acids, osteocalcin, and divalent cations.
- The physiological roles of GPRC6A remain largely uncharacterized.
Purpose of the Study:
- To investigate the physiological functions of GPRC6A by creating and analyzing GPRC6A knockout mice.
- To elucidate the role of GPRC6A in metabolic regulation and organ system function.
Main Methods:
- Generation and phenotypic characterization of GPRC6A knockout (GPRC6A(-/-)) mice.
- Assessment of metabolic parameters, including glucose tolerance, insulin resistance, body composition, and hormone levels.
- Analysis of bone mineral density, bone mineralization, and kidney function (urine composition).
Main Results:
- GPRC6A(-/-) mice display complex metabolic abnormalities across multiple organ systems.
- Observed phenotypes include hepatic steatosis, hyperglycemia, glucose intolerance, insulin resistance, and impaired bone mineralization (decreased BMD).
- Testicular GPRC6A deficiency leads to feminization in males, characterized by altered body composition and sex hormone levels (decreased testosterone, increased estradiol).
- Kidney abnormalities include altered calcium and phosphorus excretion and low molecular weight proteinuria.
Conclusions:
- GPRC6A knockout mice exhibit a metabolic syndrome encompassing defective bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance, and disordered steroidogenesis.
- These findings indicate that GPRC6A is crucial for coordinating anabolic responses in various tissues.
- GPRC6A likely functions by sensing extracellular amino acids, osteocalcin, and divalent cations to regulate systemic metabolism.
