Abstract
The G protein-coupled receptor class C, group 6, subtype A (GPRC6A) is suggested to have a physiological function in glucose and bone metabolism, although the precise role lacks consensus due to varying findings in different knockout (KO) mouse models and inconsistent findings on the role of osteocalcin, a proposed GPRC6A agonist. We have further characterized a full locus GPRC6A KO model with respect to energy metabolism, including a long-term high-dose glucocorticoid metabolic challenge. Additionally, we analyzed the microarchitecture of tibiae from young, middle-aged and aged GPRC6A KO mice and wildtype (WT) littermates. Compared to WT, vehicle-treated KO mice presented with normal body composition, unaltered insulin sensitivity and basal serum insulin and glucose levels. Corticosterone (CS) treatment resulted in insulin resistance, abnormal fat accrual, loss of lean mass and suppression of serum osteocalcin levels in both genotypes. Interestingly, serum osteocalcin and skeletal osteocalcin mRNA levels were significantly lower in vehicle-treated GPRC6A KO mice compared to WT animals. However, WT and KO age groups did not differ in long bone mass and structure assessed by micro-computed tomography. We conclude that GPRC6A is not involved in glucose metabolism under normal physiological conditions, nor does it mediate glucocorticoid-induced dysmetabolism in mice. Moreover, GPRC6A does not appear to possess a direct, non-compensable role in long bone microarchitecture under standard conditions.
Highlights
G protein-coupled receptors (GPCRs) mediate essential communication between the exterior and interior of cells
As we observed a significant reduction in osteocalcin levels in the GPRC6A KO mice under basal conditions, we determined whether the lack of GPRC6A is associated with a bone phenotype by determining the tibial microstructure of 9–12, 47–50 and 62–66-week-old full locus GPRC6A KO mice and WT littermates
Studies in an exon II KO model point towards a physiological function of the GPRC6A receptor in fuel and skeletal metabolism[8,20], while our group has found no or only subtle effects in an exon VI KO and in a full locus KO model[7,11,12,15]. While both exon knockouts should lead to a non-functional receptor, we here expand the characterization of a full locus KO model to avoid exon-specific phenotypes
Summary
G protein-coupled receptors (GPCRs) mediate essential communication between the exterior and interior of cells. The group of Quarles reported a complex dysmetabolic phenotype of their GPRC6A exon II KO mouse model, which included changes in systemic fuel metabolism, osteopenia as well as reduced testicular function in young mice[8,9]. Using the same mouse model, the group later observed reduced L-arginine-induced insulin secretion in islets isolated from GPRC6A KO mice compared to WT animals[10]. When fed a high-fat diet did GPRC6A exon VI KO mice develop a dysmetabolic phenotype compared to their WT littermates[13] In agreement with the latter observations, the group of Murphy recently reported that basal glucose levels as well as glucose tolerance were similar in WT and a GPRC6A KO model in which the full gprc6a gene had been deleted[14]. As we observed a significant reduction in osteocalcin levels in the GPRC6A KO mice under basal conditions, we determined whether the lack of GPRC6A is associated with a bone phenotype by determining the tibial microstructure of 9–12, 47–50 and 62–66-week-old full locus GPRC6A KO mice and WT littermates
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