Emerging evidence supports the hypothesis that the skeleton is also an endocrine organ that regulates energy metabolism through the release of the osteoblast-derived hormone, osteocalcin (Ocn). This novel hypothesis is controversial, because important gaps remain to be filled in our knowledge of the physiological effects of Ocn in multiple organs and the complex alterations in other hormonal networks induced by Ocn administration. Key steps toward understanding the integrative regulation of energy metabolism by bone would be to identify and characterize the function of the receptor for Ocn. We have discovered a prime candidate for the OcnR, GPRC6A, an amino-acid sensing GPCR that is highly expressed in ?-cells and is activated by recombinant Ocn in vitro and in vivo. Global ablation of GPRC6A to create OcnR-/- mice results in a phenotype that resembles Ocn-/- mice, including glucose intolerance, reductions in circulating insulin levels, and insulin resistance. Pancreatic islets isolated from OcnR-/- mice exhibit abnormalities of glucose-stimulated insulin secretion and pancreatic islet hypoplasia, suggesting that the OcnR also regulates insulin secretion and ?-cell mass. Thus, we propose to test the hypotheses that [a] this GPCR is the biologically relevant OcnR and [b] it defines a molecular mechanism for linking bone metabolism with metabolic regulation of insulin secretion and ?-cell proliferation. In addition, OcnR is also activated by L-arginine and testosterone, and recombinant Ocn regulates testosterone production by the testes, as well as metabolic functions of liver, muscle and fat, suggesting that OcnR may be a multi-liganded receptor connecting multiple endocrine networks.
The Specific Aims are to: 1) Test the specific functions of OcnR in pancreatic ?-cells by tissue-specific loss-of-function experiments in transgenic mouse models and in isolated pancreatic islets ex vivo;2) Confirm that OcnR mediates the direct effects of recombinant Ocn in pancreatic ?-cells;and 3) Determine the binding kinetics of carboxylated and undercarboxylated forms of Ocn for OcnR. Collectively these studies will define the functions of OcnR to integrate physiological networks linking bone, Ocn and other potential ligands to ?-cell functions and provide knowledge that will help to simplify the complex interdependency between the endocrine functions of bone and hormones secreted by other organs that affect bone and energy metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Appel, Michael C
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University of Tennessee Health Science Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2018) GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. Mol Nutr Food Res 62:e1700770
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2018) Computationally identified novel agonists for GPRC6A. PLoS One 13:e0195980
Pi, Min; Nishimoto, Satoru Kenneth; Quarles, L Darryl (2017) GPRC6A: Jack of all metabolism (or master of none). Mol Metab 6:185-193
Ye, Ruisong; Pi, Min; Cox, John V et al. (2017) CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. J Exp Clin Cancer Res 36:90
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2016) Evidence for Osteocalcin Binding and Activation of GPRC6A in ?-Cells. Endocrinology 157:1866-80
Pi, Min; Kapoor, Karan; Wu, Yunpeng et al. (2015) Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Mol Endocrinol 29:1759-73
Quarles, L Darryl (2013) Reducing cardiovascular mortality in chronic kidney disease: something borrowed, something new. J Clin Invest 123:542-3
Pi, Min; Quarles, L Darryl (2013) Novel bone endocrine networks integrating mineral and energy metabolism. Curr Osteoporos Rep 11:391-9
Pi, Min; Quarles, L Darryl (2012) GPRC6A regulates prostate cancer progression. Prostate 72:399-409
Pi, Min; Quarles, L Darryl (2012) Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153:2062-9

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