GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome.
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.


RESULTS
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
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.
Pi
Min
M
The Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
Chen
Ling
L
Huang
Min-Zhao
MZ
Zhu
Wenyu
W
Ringhofer
Brian
B
Luo
Junming
J
Christenson
Lane
L
Li
Benyi
B
Zhang
Jianghong
J
Jackson
P David
PD
Faber
Pieter
P
Brunden
Kurt R
KR
Harrington
John J
JJ
Quarles
L Darryl
LD
D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D005262:Feminization / Q000235:genetics*; D017353:Gene Deletion; D015870:Gene Expression; D012739:Gonadal Steroid Hormones / Q000097:blood; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout / Q000002:abnormalities; D009139:Musculoskeletal Abnormalities; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515750:GPRC6A protein, mouse; D012739:Gonadal Steroid Hormones; D007328:Insulin; D043562:Receptors, G-Protein-Coupled