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Min Pi, Satoru Kenneth Nishimoto, L Darryl Quarles
BACKGROUND: GPRC6A, a widely expressed G-protein coupled receptor, is proposed to be a master regulator of complex endocrine networks and metabolic processes. GPRC6A is activated by multiple ligands, including osteocalcin (Ocn), testosterone (T), basic amino acids, and various cations. SCOPE OF REVIEW: We review the controversy surrounding GPRC6A functions. In mice, GPRC6A is proposed to integrate metabolic functions through the coordinated secretion of hormones, including insulin, GLP-1, T, and IL-6, and direct effects of this receptor to control glucose and fat metabolism in the liver, skeletal muscle, and fat...
February 2017: Molecular Metabolism
Stine Jørgensen, Christian Theil Have, Christina Rye Underwood, Lars Dan Johansen, Petrine Wellendorph, Anette Prior Gjesing, Christinna V Jørgensen, Shi Quan, Gao Rui, Asuka Inoue, Allan Linneberg, Niels Grarup, Wang Jun, Oluf Pedersen, Torben Hansen, Hans Bräuner-Osborne
GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional...
January 27, 2017: Journal of Biological Chemistry
Christoffer Clemmensen, Christinna V Jørgensen, Sanela Smajilovic, Hans Bräuner-Osborne
The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation...
December 10, 2016: Diabetes, Obesity & Metabolism
Claudia Camerino, Elena Conte, Maria Cannone, Roberta Caloiero, Adriano Fonzino, Domenico Tricarico
Nerve Growth Factor (NGF)/Brain-derived Neurotrophic Factor (BDNF) and osteocalcin share common effects regulating energy, bone mass, reproduction and neuronal functions. To investigate on the gene-relationship between NGF, BDNF, and Osteocalcin we compared by RT-PCR the transcript levels of Ngf, Bdnf and Osteocalcin as well as of their receptors p75NTR/NTRK1, NTRK2, and Gprc6a in brain, bone, white/brown adipose tissue (WAT/BAT) and reproductive organs of 3 months old female and male mice. Brain and bone were used as positive controls for NGF/BDNF and Osteocalcin respectively...
2016: Frontiers in Physiology
Bianca Ferreira Olivieri, Maria Eugênia Zerlotti Mercadante, Joslaine Noely Dos Santos Gonçalves Cyrillo, Renata Helena Branco, Sarah Figueiredo Martins Bonilha, Lucia Galvão de Albuquerque, Rafael Medeiros de Oliveira Silva, Fernando Baldi
The objective of this study was to identify genomic regions and metabolic pathways associated with dry matter intake, average daily gain, feed efficiency and residual feed intake in an experimental Nellore cattle population. The high-density SNP chip (Illumina High-Density Bovine BeadChip, 777k) was used to genotype the animals. The SNP markers effects and their variances were estimated using the single-step genome wide association method. The (co)variance components were estimated by Bayesian inference. The chromosome segments that are responsible for more than 1...
2016: PloS One
Andrea Di Nisio, Maria Santa Rocca, Gian Paolo Fadini, Luca De Toni, Giorgio Marcuzzo, Maria Cristina Marescotti, Marta Sanna, Mario Plebani, Roberto Vettor, Angelo Avogaro, Carlo Foresta
OBJECTIVE: Identification of the novel endocrine role of osteocalcin (OC) and its receptor GPRC6A has given rise to a new branch of research in OC/GPRC6A axis related to glucose metabolism. GPRC6A- and OC-deficient mice share features of the metabolic syndrome, in addition to male infertility. Recently, the polymorphism rs2274911 in GPRC6A was shown to be associated with testicular impairment. We aimed to investigate the role of rs2274911 polymorphism in glucose and lipid metabolism in a cohort of normal weight and obese subjects DESIGN, PATIENTS, SETTINGS: A total of 392 male and females, including 218 obese patients and 174 age-matched normal weight controls, were retrospectively selected...
October 1, 2016: Clinical Endocrinology
Paula Mera, Kathrin Laue, Jianwen Wei, Julian Meyer Berger, Gerard Karsenty
OBJECTIVE: A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone osteocalcin decline steeply during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. METHODS: We examined muscle mass and strength in mice lacking osteocalcin (Ocn-/-) or its receptor in all cells (Gprc6a-/-) or specifically in myofibers (Gprc6a Mck -/-) as well as in 9 month-old WT mice receiving exogenous osteocalcin for 28 days...
October 2016: Molecular Metabolism
Luca De Toni, Diego Guidolin, Vincenzo De Filippis, Simone Tescari, Giacomo Strapazzon, Maria Santa Rocca, Alberto Ferlin, Mario Plebani, Carlo Foresta
The undercarboxylated form of osteocalcin (ucOC) regulates male fertility and energy metabolism, acting through the G protein-coupled receptor GPRC6A thus forming a new pancreas-bone-testis axis. Recently, GPRC6A has also been suggested to mediate the non-genomic responses of free testosterone (T). However, these data did not consider the physiological scenario, where circulating T is mainly bound to sex hormone-binding globulin (SHBG) and only a small percentage circulates freely in the blood. Here, by the use of computational modelling, we document the existence of similar structural moieties between ucOC and SHBG that are predicted to bind to GPRC6A at docking analysis...
September 27, 2016: Endocrinology
M Liu, Y-Y Zhao, F Yang, J-Y Wang, X-H Shi, X-Q Zhu, Y Xu, D Wei, L Sun, Y-G Zhang, K Yang, Y-C Qu, X Wang, S-Y Liang, X Chen, C-X Zhao, L Zhu, L Tang, C-G Zheng, Z Yang
OBJECTIVE: G protein-coupled receptor, family C, group 6, member A, (GPRC6A) is a prostate cancer (PCa) susceptibility gene and has been shown to regulate PCa progression. However, its role in PCa metastasis is largely unknown. The aim of this study was to confirm the association between GPRC6A and aggressive PCa in a case-control analysis, and to explore the function of GPRC6A in PCa metastasis in vitro. PATIENTS AND METHODS: The association of 14 single nucleotide polymorphisms (SNPs) of GPRC6A and linked to GPRC6A were evaluated with PCa risk and aggressive PCa in 916 subjects...
June 2016: European Review for Medical and Pharmacological Sciences
Sujeenthar Tharmalingam, David R Hampson
The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor...
2016: Frontiers in Physiology
Xuzhu Lin, Erik Hanson, Andrew C Betik, Tara C Brennan-Speranza, Alan Hayes, Itamar Levinger
Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery...
June 13, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Thierry Capiod
Calcium channels and the two G-protein coupled receptors sensing extracellular calcium, calcium-sensing receptor (CaSR) and GPRC6a, are the two main means by which extracellular calcium can signal to cells and regulate many cellular processes including cell proliferation, migration and invasion of tumoral cells. Many intracellular signaling pathways are sensitive to cytosolic calcium rises and conversely intracellular signaling pathways can modulate calcium channel expression and activity. Calcium channels are undoubtedly involved in the former while the CaSR and GPRC6a are most likely to interfere with the latter...
2016: Advances in Experimental Medicine and Biology
Min Pi, Karan Kapoor, Ruisong Ye, Satoru Kenneth Nishimoto, Jeremy C Smith, Jerome Baudry, Leigh Darryl Quarles
The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A...
May 2016: Endocrinology
Jing Du, Mingliang Zhang, Junxi Lu, Xueli Zhang, Qin Xiong, Yiting Xu, Yuqian Bao, Weiping Jia
Recent studies have demonstrated a protective effect of osteocalcin against nonalcoholic fatty liver disease (NAFLD), although the specific underlying mechanisms remain unclear. Nrf2 and JNK pathways play important roles in the pathogenesis of NAFLD. The present study aimed to investigate whether osteocalcin protects against NAFLD by regulating these pathways. Male C57/BL6J mice were fed a high-fat diet for 12 weeks to induce NAFLD and were treated with recombinant decarboxylate osteocalcin (30 ng/g) or vehicle by daily intraperitoneal injection during this period...
September 2016: Endocrine
A Alamshah, A K McGavigan, E Spreckley, J S Kinsey-Jones, A Amin, I R Tough, H C O'Hara, A Moolla, K Banks, R France, G Hyberg, M Norton, W Cheong, A Lehmann, S R Bloom, H M Cox, K G Murphy
AIMS: To investigate the anorectic effect of L-arginine (L-Arg) in rodents. METHODS: We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. RESULTS: Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice...
May 2016: Diabetes, Obesity & Metabolism
Patricia Rueda, Elizabeth Harley, Yao Lu, Gregory D Stewart, Stewart Fabb, Natalie Diepenhorst, Béatrice Cremers, Marie-Hélène Rouillon, Isabelle Wehrle, Anne Geant, Gwladys Lamarche, Katie Leach, William N Charman, Arthur Christopoulos, Roger J Summers, Patrick M Sexton, Christopher J Langmead
Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive...
2016: PloS One
Jinqiao Li, Hongyu Zhang, Chao Yang, Yinghui Li, Zhongquan Dai
An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the detailed functions and mechanism of osteocalcin are not well understood and conflicting results have been obtained from researchers worldwide. In the present review, we summarize the progress of osteocalcin studies over the past 40 years, focusing on the structure of carboxylated and undercarboxylated osteocalcin, new functions and putative receptors, the role of osteocalcin in bone remodeling, specific expression and regulation in osteoblasts, and new indices for clinical studies...
July 2016: Journal of Bone and Mineral Metabolism
Luca De Toni, Andrea Di Nisio, Elena Speltra, Maria Santa Rocca, Marco Ghezzi, Daniela Zuccarello, Nunzio Turiaco, Alberto Ferlin, Carlo Foresta
CONTEXT: The G protein-coupled receptor GPRC6A is an emerging effector with multiple endocrine roles, including stimulation of T production from the testis. Recently, two men with an inactivating mutation (F464Y) of GPRC6A have been identified, and they showed primary testicular failure and deranged spermatogenesis. Furthermore, one of them also reported cryptorchidism at birth. In addition, a polymorphism (rs2274911, Pro91Ser) in GPRC6A is associated with prostate cancer, a typical androgen-sensitive cancer...
March 2016: Journal of Clinical Endocrinology and Metabolism
Dagmar Quandt, Kathrin Rothe, Christoph Baerwald, Manuela Rossol
Alum adjuvanticity is still an unknown mechanism despite the frequent use as vaccine adjuvant in humans. Here we show that Alum-induced inflammasome activation in vitro and in vivo is mediated by the G protein-coupled receptor GPRC6A. The Alum-induced humoral response in vivo was independent of the inflammasome because Nlrp3-/- and ASC-/- mice responded normally to Alum and blockade of IL-1 had no effect on antibody production. In contrast, Alum adjuvanticity was increased in GPRC6A-/- mice resulting in increased antibody responses and increased Th2 cytokine concentrations compared to wildtype mice...
November 25, 2015: Scientific Reports
Xing-Hui Li, Yong Xu, Kuo Yang, Jian-Jian Shi, Xiao Zhang, Fang Yang, Huiping Yuan, Xiaoquan Zhu, Yu-Hong Zhang, Jian-Ye Wang, Ze Yang
PURPOSE: Prostate cancer (PCa) is one of the most common malignancies in males, and multiple genetic studies have confirmed association with susceptibility to PCa. However, the risk conferred in men living in China is unkown. We selected 6 previously identified variants as candidates to define their association with PCa in Chinese men. METHODS: We genotyped 6 single nucleotide polymorphisms (SNPs) (rs1465618, rs1983891, rs339331, rs16901966, rs1447295 and rs10090154) using high resolution melting (HRM) analysis and assessed their association with PCa risk in a case-control study of 481 patients and 480 controls in a Chinese population...
September 2015: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
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