Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks

Research output: Contribution to journalReview article

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Abstract

Emerging evidence supports the hypothesis that the skeleton is an endocrine organ that regulates energy metabolism through the release of the osteoblast-derived hormone, osteocalcin (Ocn). This bone-pancreas endocrine network 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. A key step toward understanding the integrative regulation of energy metabolism by bone is the identification of GPCR family C group 6 member A (GPRC6A) as the Ocn receptor. GPRC6A is an amino acid-sensing G protein-coupled receptor highly expressed in β-cells and is activated by recombinant Ocn in vitro and in vivo but that is widely expressed in tissues other than the pancreas and is capable of sensing multiple structurally unrelated ligands, including L-amino acids, cations, and anabolic steroids in addition to Ocn. The broad expression and multiligand specificity of GPRC6A is identifying both systemic and paracrine regulation of seemingly disparate biological processes, ranging from energy metabolism, sexual reproduction, hypothalamic-pituitary function, bone formation, and prostate cancer. Consistent with the existence of more complex endocrine networks, ablation of GPRC6A in Gprc6a -/- mice results in complex metabolic abnormalities, including obesity, glucose intolerance, hepatic steatosis, insulin resistance, hyperphosphatemia, osteopenia, plus several hormonal abnormalities, including decreased circulating testosterone, IGF-I, and insulin and increased estradiol, LH, GH, and leptin. Recombinant Ocn also regulates testosterone production by the testes and male fertility through a GPRC6A-dependent mechanism, and testosterone regulation of LH secretion is abnormal in Gprc6a -/- mice. Thus, GPRC6A, as the biologically relevant receptor for Ocn, defines not only a molecular mechanism for linking bone metabolism with metabolic regulation of β-cells and sexual reproduction but also as a receptor shared by testosterone and dietary factors, and it is also involved in multiple endocrine networks integrating the functions of pancreas, muscle, liver, fat, testes, bone, and the hypothalamic-pituitary axis with alterations in both environmental and endogenous ligands.

Original languageEnglish (US)
Pages (from-to)2062-2069
Number of pages8
JournalEndocrinology
Volume153
Issue number5
DOIs
StatePublished - May 1 2012

Fingerprint

Organ Specificity
Osteocalcin
Energy Metabolism
Testosterone
Bone and Bones
Reproduction
Testis
Pancreas
Testosterone Congeners
Ligands
Hyperphosphatemia
Biological Phenomena
Amino Acids
Bone Neoplasms
Glucose Intolerance
Metabolic Bone Diseases
Liver
Androgen Receptors
G-Protein-Coupled Receptors
Leptin

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. / Pi, Min; Quarles, Leigh.

In: Endocrinology, Vol. 153, No. 5, 01.05.2012, p. 2062-2069.

Research output: Contribution to journalReview article

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