Explaining Divergent Observations Regarding Osteocalcin/GPRC6A Endocrine Signaling

Abstract

A new schema proposes that the bone-derived osteocalcin (Ocn) peptide hormone activates the G- protein coupled receptor GPRC6A to directly regulate glucose and fat metabolism in liver, muscle and fat, and to stimulate the release of metabolism-regulating hormones, including insulin, fibroblast growth factor 21, glucagon-like peptide 1, testosterone and interleukin 6. Ocn/GPRC6A activation has also been implicated in cancer progression. GPRC6Ais activated by cations, amino acids and testosterone. The multi-ligand specificity, the regulation of energy metabolism in diverse tissues and the coordinated release of metabolically active hormones make the GPRC6A endocrine networks unique. Recently the significance of Ocn/GPRCA have been questioned. There is a lack of metabolic abnormalities in newly created genetically engineered Ocn- and Gprc6a-deficient mouse models. There are also paradoxical observations that GPRC6A may function as a tumor suppressor. In addition, discordant published studies have cast doubt on the function of the most prevalent uniquely human GPRC6A-KGKY polymorphism. Explanations for these divergent findings are elusive. We provide evidence that the metabolic susceptibility of genetically engineered Ocn- and Gprc6a-deficient mice is influenced by environmental challenges and genetic differences in mouse strains. In addition, the GPRC6A-KGKY polymorphism appears to be a gain-of-function variant. Finally, alternatively spliced isoforms of GPRC6A may alter ligand specificity and signaling that modulate oncogenic effects. Thus, genetic, post-translational and environmental factors likely account for the variable results regarding the functions of GPRC6A in animal models. Pending additional information, GPRC6A should remain a potential therapeutic target for regulating energy and fat metabolism, hormone production, and cancer progression.

Protein- and Calcium-Mediated GLP-1 Secretion: A Narrative Review

“…Despite this, utilizing a rodent GPRC6A whole-body knockout model, oral administration of both l -arginine and l -ornithine significantly increased plasma GLP-1 TOTAL to a comparable magnitude in GPRC6A knockout and wild-type mice ( 138 ). However, as extensively discussed by Pi et al ( 133 , 139 ), caution should be taken when analyzing the reported effects. GPRC6A mouse knockout models are challenging due to variations in metabolic phenotype ( 140 , 141 ), which are reportedly influenced by environmental challenges and genetic differences in mouse strains ( 139 ).…”

“…However, as extensively discussed by Pi et al ( 133 , 139 ), caution should be taken when analyzing the reported effects. GPRC6A mouse knockout models are challenging due to variations in metabolic phenotype ( 140 , 141 ), which are reportedly influenced by environmental challenges and genetic differences in mouse strains ( 139 ). In addition, the translational validity of such studies is questioned because GPRC6A (in humans) presents an evolutionarily divergent genotype characterized by a gain-of-function polymorphism (GPRC6A KGKY ), which might alter the role of this receptor ( 133 ).…”

Osteocalcin and the physiology of danger

“…Yet, probably the most critical consequence of the identification of Gprc6a as a receptor of osteocalcin has been to allow the study of the biology of osteocalcin in humans as will be described below. More broadly, it gave to osteocalcin a more complete hormonal identity, which has now been confirmed by numerous independent cell culture studies, in vivo studies in multiple species and multiple disease models, by correlative studies in humans and as we will describe, human genetic evidence [37,42,45–120]. It was also confirmed even more recently by the generation of a new genetic model of Osteocalcin deficiency [50].…”

Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse

“…As for GC, they affect numerous physiological processes through their ability to modulate gene expression in a wide array of cell types (11,12). In the skeleton, GC are powerful inhibitors of Osteocalcin expression in osteoblasts, a regulation that was puzzling until evidence that osteocalcin is a hormone accumulated (13,14). Indeed, given the endocrine identity of osteocalcin, the inhibition of its expression by GC suggests that through a classical feedback loop osteocalcin may be a previously unappreciated physiological regulator of GC biosynthesis.…”