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https://www.readbyqxmd.com/read/29684031/computationally-identified-novel-agonists-for-gprc6a
#1
Min Pi, Karan Kapoor, Ruisong Ye, Dong-Jin Hwang, Duane D Miller, Jeremy C Smith, Jerome Baudry, L Darryl Quarles
New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance...
2018: PloS One
https://www.readbyqxmd.com/read/29468843/gpcr6a-is-a-molecular-target-for-the-natural-products-gallate-and-egcg-in-green-tea
#2
Min Pi, Karan Kapoor, Ruisong Ye, Jeremy C Smith, Jerome Baudry, Leigh D Quarles
SCOPE: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood. METHODS AND RESULTS: We found that GPRC6A, a multi-ligand-sensing G-protein-coupled receptor that regulates energy metabolism, sex hormone production, and prostate cancer progression, is a target for gallates. Sodium gallate (SG), gallic acid (GA) > ethyl gallate (EG) > octyl gallate (OG) dose dependently activated ERK in HEK-293 cells transfected with GPRC6A but not in non-transfected controls...
April 2018: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29358218/tcf7-tcf1-feedback-controls-osteocalcin-signaling-in-brown-adipocytes-independent-of-canonical-wnt-%C3%AE-catenin-pathway
#3
Qian Li, Yue Hua, Yilin Yang, Xinyu He, Wei Zhu, Jiyong Wang, Xiaoqing Gan
Osteocalcin has recently been shown to regulate energy homeostasis through multiple pathways. Adipose tissue is a main organ of energy metabolism, and administration of recombinant osteocalcin in mice promoted energy consumption, thus counteracting obesity and glucose intolerance. The regulation of osteocalcin in islet β cells has been well documented; however, it is unknown whether osteocalcin can also act on adipocytes, and if does, how it functions. Here, we provided evidence to demonstrate a specific role for osteocalcin in brown adipocyte thermogenesis...
January 22, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29194451/adiponectin-receptor-1-resists-the-decline-of-serum-osteocalcin-and-gprc6a-expression-in-ovariectomized-mice
#4
Yuan-Yu Lin, Ching-Yi Chen, Shih-Torng Ding
Hormonal changes that cause metabolic complications are a common problem in postmenopausal women. Adiponectin and osteocalcin are cytokines associated with glucose regulatory and insulin sensitized function in postmenopausal stages. The current study investigated the role of adiponectin signaling and osteocalcin mediated function in glucose metabolism in ovariectomized mice. In a mouse menopausal-related metabolic disorder model, overexpression of adiponectin receptor 1 improved glucose tolerance and caused resistance to body weight increase and decline of serum osteocalcin...
2017: PloS One
https://www.readbyqxmd.com/read/29167276/pten-loss-promotes-intratumoral-androgen-synthesis-and-tumor-microenvironment-remodeling-via-aberrant-activation-of-runx2-in-castration-resistant-prostate-cancer
#5
Yinhui Yang, Yang Bai, Yundong He, Yu Zhao, Jiaxiang Chen, Linlin Ma, Yunqian Pan, Michael Hinten, Jun Zhang, R Jeffrey Karnes, Manish Kohli, Jennifer J Westendorf, Benyi Li, Runzhi Zhu, Haojie Huang, Wanhai Xu
Purpose: Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR) reactivation and antiandrogen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design: The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human prostate cancer cell lines...
February 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28977794/osteocalcin-induces-proliferation-via-positive-activation-of-the-pi3k-akt-p38-mapk-pathways-and-promotes-differentiation-through-activation-of-the-gprc6a-erk1-2-pathway-in-c2c12-myoblast-cells
#6
Suifeng Liu, Feng Gao, Lei Wen, Min Ouyang, Yi Wang, Qiong Wang, Liping Luo, Zaijin Jian
BACKGROUND/AIMS: Sarcopenia is characterized by an age-related decline in skeletal muscle plus low muscle strength and/or physical performance. Despite the clinical significance of sarcopenia, the molecular pathways underlying sarcopenia remain elusive. The recent demonstration that undercarboxylated osteocalcin (ucOC) favours muscle function related to insulin sensitivity and glucose metabolism raises the question of whether this hormone may also regulate muscle mass. The present study explored the promotive effects of ucOC in proliferation and differentiation processes of C2C12 myoblasts as well as the possible signalling pathways involved...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28659174/crispr-cas9-targeting-of-gprc6a-suppresses-prostate-cancer-tumorigenesis-in-a-human-xenograft-model
#7
Ruisong Ye, Min Pi, John V Cox, Satoru K Nishimoto, L Darryl Quarles
BACKGROUND: GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species. METHODS: We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a "humanized" mouse GPRC6A containing the K...
June 28, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28559246/neprilysin-is-required-for-angiotensin-1-7-s-ability-to-enhance-insulin-secretion-via-its-proteolytic-activity-to-generate-angiotensin-1-2
#8
Gurkirat S Brar, Breanne M Barrow, Matthew Watson, Ryan Griesbach, Edwina Choung, Andrew Welch, Bela Ruzsicska, Daniel P Raleigh, Sakeneh Zraika
Recent work has renewed interest in therapies targeting the renin-angiotensin system (RAS) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS...
August 2017: Diabetes
https://www.readbyqxmd.com/read/28428077/molecular-bases-of-the-crosstalk-between-bone-and-muscle
#9
Gerard Karsenty, Paula Mera
Exercise is an evolutionary conserved survival function that nowadays has beneficial health effects. The increased metabolic activity of contracting skeletal muscle affects the biology of many organs involved in regulating muscle functions. The discovery of hormones and cytokines secreted by bone and skeletal muscle during exercise, has recently added experimental credence to the notion that a crosstalk exists between these organs. Bone through the hormone osteocalcin, promotes exercise capacity in the mouse...
April 18, 2017: Bone
https://www.readbyqxmd.com/read/28395130/osteocalcin-a-bone-derived-hormone-with-important-andrological-implications
#10
REVIEW
L De Toni, A Di Nisio, M S Rocca, M De Rocco Ponce, A Ferlin, C Foresta
Increasing evidence disclosed the existence of a novel multi-organ endocrine pathway, involving bone, pancreas and testis, of high penetrance in energy metabolism and male fertility. The main mediator of this axis is undercarboxylated osteocalcin (ucOC), a bone-derived protein-exerting systemic effects on tissues expressing the metabotropic receptor GPRC6A. The recognized effects of ucOC are the improvement of insulin secretion from the pancreas, the amelioration of systemic insulin sensitivity, in particular in skeletal muscle, and the stimulation of the global endocrine activity of the Leydig cell, including vitamin D 25-hydroxylation and testosterone production...
July 2017: Andrology
https://www.readbyqxmd.com/read/28180060/gprc6a-jack-of-all-metabolism-or-master-of-none
#11
REVIEW
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
https://www.readbyqxmd.com/read/27986810/genetic-variations-in-the-human-g-protein-coupled-receptor-class-c-group-6-member-a-gprc6a-control-cell-surface-expression-and-function
#12
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
https://www.readbyqxmd.com/read/27943578/robust-glp-1-secretion-by-basic-l-amino-acids-does-not-require-the-gprc6a-receptor
#13
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...
April 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27790153/nerve-growth-factor-brain-derived-neurotrophic-factor-and-osteocalcin-gene-relationship-in-energy-regulation-bone-homeostasis-and-reproductive-organs-analyzed-by-mrna-quantitative-evaluation-and-linear-correlation-analysis
#14
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
https://www.readbyqxmd.com/read/27760167/genomic-regions-associated-with-feed-efficiency-indicator-traits-in-an-experimental-nellore-cattle-population
#15
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
https://www.readbyqxmd.com/read/27696500/the-rs2274911-polymorphism-in-gprc6a-gene-is-associated-with-insulin-resistance-in-normal-weight-and-obese-subjects
#16
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...
February 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/27689017/osteocalcin-is-necessary-and-sufficient-to-maintain-muscle-mass-in-older-mice
#17
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
https://www.readbyqxmd.com/read/27673554/osteocalcin-and-sex-hormone-binding-globulin-compete-on-a-specific-binding-site-of-gprc6a
#18
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 (GPRC)6A, thus forming a new pancreas-bone-testis axis. Recently, GPRC6A has also been suggested to mediate the nongenomic 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...
November 2016: Endocrinology
https://www.readbyqxmd.com/read/27338047/evidence-for-a-role-of-gprc6a-in-prostate-cancer-metastasis-based-on-case-control-and-in-vitro-analyses
#19
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
https://www.readbyqxmd.com/read/27303307/the-calcium-sensing-receptor-and-integrins-in-cellular-differentiation-and-migration
#20
REVIEW
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
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