GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome
GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown. In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metab...
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| Veröffentlicht in: | PloS one 2008-12, Vol.3 (12), p.e3858-e3858 |
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| creator | Pi, Min Chen, Ling Huang, Min-Zhao Zhu, Wenyu Ringhofer, Brian Luo, Junming Christenson, Lane Li, Benyi Zhang, Jianghong Jackson, P David Faber, Pieter Brunden, Kurt R Harrington, John J Quarles, L Darryl |
| description | GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.
In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.
GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations. |
| doi_str_mv | 10.1371/journal.pone.0003858 |
| format | Article |
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In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.
GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0003858</identifier><identifier>PMID: 19050760</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>17β-Estradiol ; Abnormalities ; Amino acids ; Animal tissues ; Animals ; Biocompatibility ; Biomedical materials ; Blotting, Western ; Body fat ; Body mass ; Bone and Bones - metabolism ; Bone density ; Bone Density - genetics ; Bone Diseases, Metabolic - genetics ; Bone mineral density ; Calcium ; Cations ; Cell Biology ; Diabetes and Endocrinology/Bone and Mineral Metabolism ; Diabetes and Endocrinology/Obesity ; Diabetes and Endocrinology/Reproductive Endocrinology ; Distal tubules ; Divalent cations ; Estradiol ; Exhibitions ; Fatty liver ; Fatty Liver - genetics ; Female ; Feminization ; Feminization - genetics ; G protein-coupled receptors ; Gastroenterology and Hepatology/Hepatology ; Gene Deletion ; Gene Expression ; Genotype & phenotype ; Glucose ; Glucose tolerance ; Gonadal Steroid Hormones - blood ; Hyperglycemia ; Insulin ; Insulin - metabolism ; Insulin resistance ; Intolerance ; Kidney - abnormalities ; Kidney - physiopathology ; Kidneys ; Lean body mass ; Leydig cells ; Liver ; Liver diseases ; Low molecular weights ; Male ; Metabolic disorders ; Metabolic syndrome ; Metabolic Syndrome - genetics ; Metabolism ; Mice ; Mice, Knockout - abnormalities ; Mineralization ; Molecular weight ; Musculoskeletal Abnormalities ; Nephrology/Mineral Metabolism and the Kidney ; Osteoporosis ; Phenotype ; Phenotypes ; Phosphorus ; Physiological aspects ; Physiology ; Physiology/Endocrinology ; Proteins ; Proteinuria ; Proximal tubules ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - physiology ; Renal function ; Reverse Transcriptase Polymerase Chain Reaction ; Rodents ; Scholarships & fellowships ; Sex hormones ; Testes ; Testosterone ; Transcription factors ; Urine</subject><ispartof>PloS one, 2008-12, Vol.3 (12), p.e3858-e3858</ispartof><rights>COPYRIGHT 2008 Public Library of Science</rights><rights>2008 Pi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Pi et al. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c759t-b4f81c07c65a3d961e1acc29d5b7266b0a1e14268bb59fc245ead922ed7db58e3</citedby><cites>FETCH-LOGICAL-c759t-b4f81c07c65a3d961e1acc29d5b7266b0a1e14268bb59fc245ead922ed7db58e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585477/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585477/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19050760$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Calbet, Jose A. L.</contributor><creatorcontrib>Pi, Min</creatorcontrib><creatorcontrib>Chen, Ling</creatorcontrib><creatorcontrib>Huang, Min-Zhao</creatorcontrib><creatorcontrib>Zhu, Wenyu</creatorcontrib><creatorcontrib>Ringhofer, Brian</creatorcontrib><creatorcontrib>Luo, Junming</creatorcontrib><creatorcontrib>Christenson, Lane</creatorcontrib><creatorcontrib>Li, Benyi</creatorcontrib><creatorcontrib>Zhang, Jianghong</creatorcontrib><creatorcontrib>Jackson, P David</creatorcontrib><creatorcontrib>Faber, Pieter</creatorcontrib><creatorcontrib>Brunden, Kurt R</creatorcontrib><creatorcontrib>Harrington, John J</creatorcontrib><creatorcontrib>Quarles, L Darryl</creatorcontrib><title>GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.
In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.
GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.</description><subject>17β-Estradiol</subject><subject>Abnormalities</subject><subject>Amino acids</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>Blotting, Western</subject><subject>Body fat</subject><subject>Body mass</subject><subject>Bone and Bones - metabolism</subject><subject>Bone density</subject><subject>Bone Density - genetics</subject><subject>Bone Diseases, Metabolic - genetics</subject><subject>Bone mineral density</subject><subject>Calcium</subject><subject>Cations</subject><subject>Cell Biology</subject><subject>Diabetes and Endocrinology/Bone and Mineral Metabolism</subject><subject>Diabetes and Endocrinology/Obesity</subject><subject>Diabetes and Endocrinology/Reproductive Endocrinology</subject><subject>Distal tubules</subject><subject>Divalent cations</subject><subject>Estradiol</subject><subject>Exhibitions</subject><subject>Fatty liver</subject><subject>Fatty Liver - genetics</subject><subject>Female</subject><subject>Feminization</subject><subject>Feminization - genetics</subject><subject>G protein-coupled receptors</subject><subject>Gastroenterology and Hepatology/Hepatology</subject><subject>Gene Deletion</subject><subject>Gene Expression</subject><subject>Genotype & phenotype</subject><subject>Glucose</subject><subject>Glucose tolerance</subject><subject>Gonadal Steroid Hormones - blood</subject><subject>Hyperglycemia</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin resistance</subject><subject>Intolerance</subject><subject>Kidney - abnormalities</subject><subject>Kidney - physiopathology</subject><subject>Kidneys</subject><subject>Lean body mass</subject><subject>Leydig cells</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Low molecular weights</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Metabolic Syndrome - genetics</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Knockout - abnormalities</subject><subject>Mineralization</subject><subject>Molecular weight</subject><subject>Musculoskeletal Abnormalities</subject><subject>Nephrology/Mineral Metabolism and the Kidney</subject><subject>Osteoporosis</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Phosphorus</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Physiology/Endocrinology</subject><subject>Proteins</subject><subject>Proteinuria</subject><subject>Proximal tubules</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - physiology</subject><subject>Renal function</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Rodents</subject><subject>Scholarships & fellowships</subject><subject>Sex hormones</subject><subject>Testes</subject><subject>Testosterone</subject><subject>Transcription 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Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pi, Min</au><au>Chen, Ling</au><au>Huang, Min-Zhao</au><au>Zhu, Wenyu</au><au>Ringhofer, Brian</au><au>Luo, Junming</au><au>Christenson, Lane</au><au>Li, Benyi</au><au>Zhang, Jianghong</au><au>Jackson, P David</au><au>Faber, Pieter</au><au>Brunden, Kurt R</au><au>Harrington, John J</au><au>Quarles, L Darryl</au><au>Calbet, Jose A. L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2008-12-03</date><risdate>2008</risdate><volume>3</volume><issue>12</issue><spage>e3858</spage><epage>e3858</epage><pages>e3858-e3858</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.
In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.
GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19050760</pmid><doi>10.1371/journal.pone.0003858</doi><tpages>e3858</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2008-12, Vol.3 (12), p.e3858-e3858 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1312317036 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PLoS - Public Library of Sciencem (Open Access); Free E-Journal (出版社公開部分のみ）; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 17β-Estradiol Abnormalities Amino acids Animal tissues Animals Biocompatibility Biomedical materials Blotting, Western Body fat Body mass Bone and Bones - metabolism Bone density Bone Density - genetics Bone Diseases, Metabolic - genetics Bone mineral density Calcium Cations Cell Biology Diabetes and Endocrinology/Bone and Mineral Metabolism Diabetes and Endocrinology/Obesity Diabetes and Endocrinology/Reproductive Endocrinology Distal tubules Divalent cations Estradiol Exhibitions Fatty liver Fatty Liver - genetics Female Feminization Feminization - genetics G protein-coupled receptors Gastroenterology and Hepatology/Hepatology Gene Deletion Gene Expression Genotype & phenotype Glucose Glucose tolerance Gonadal Steroid Hormones - blood Hyperglycemia Insulin Insulin - metabolism Insulin resistance Intolerance Kidney - abnormalities Kidney - physiopathology Kidneys Lean body mass Leydig cells Liver Liver diseases Low molecular weights Male Metabolic disorders Metabolic syndrome Metabolic Syndrome - genetics Metabolism Mice Mice, Knockout - abnormalities Mineralization Molecular weight Musculoskeletal Abnormalities Nephrology/Mineral Metabolism and the Kidney Osteoporosis Phenotype Phenotypes Phosphorus Physiological aspects Physiology Physiology/Endocrinology Proteins Proteinuria Proximal tubules Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - physiology Renal function Reverse Transcriptase Polymerase Chain Reaction Rodents Scholarships & fellowships Sex hormones Testes Testosterone Transcription factors Urine |
| title | GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome |
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