{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:56:27Z","timestamp":1789754187780,"version":"4.0.1"},"reference-count":26,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":2937,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,9,1]]},"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder with diverse pathological manifestations and is often associated with abnormal regulation of hepatic glucose production. Many nuclear receptors known to control the hepatic gluconeogenic program are potential targets for the treatment of T2DM and its complications. Nevertheless, the therapeutic potential of the estrogen-related receptor \u03b3 (ERR\u03b3) in T2DM remains unknown. In this study, we show that the nuclear receptor ERR\u03b3 is a major contributor to hyperglycemia under diabetic conditions by controlling hepatic glucose production. Hepatic ERR\u03b3 expression induced by fasting and diabetic conditions resulted in elevated levels of gluconeogenic gene expression and blood glucose in wild-type mice. Conversely, ablation of hepatic ERR\u03b3 gene expression reduced the expression of gluconeogenic genes and normalized blood glucose levels in mouse models of T2DM: db\/db and diet-induced obesity (DIO) mice. In addition, a hyperinsulinemic-euglycemic clamp study and long-term studies of the antidiabetic effects of GSK5182, the ERR\u03b3-specific inverse agonist, in db\/db and DIO mice demonstrated that GSK5182 normalizes hyperglycemia mainly through inhibition of hepatic glucose production. Our findings suggest that the ability of GSK5182 to control hepatic glucose production can be used as a novel therapeutic approach for the treatment of T2DM.<\/jats:p>","DOI":"10.2337\/db12-0946","type":"journal-article","created":{"date-parts":[[2013,6,18]],"date-time":"2013-06-18T04:51:19Z","timestamp":1371531079000},"page":"3093-3102","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":73,"title":["Inverse Agonist of Nuclear Receptor ERR\u03b3 Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis"],"prefix":"10.2337","volume":"62","author":[{"given":"Don-Kyu","family":"Kim","sequence":"first","affiliation":[{"name":"National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil-Tae","family":"Gang","sequence":"additional","affiliation":[{"name":"Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongryeol","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Korea University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minseob","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo-Na","family":"Kim","sequence":"additional","affiliation":[{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Korea University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taebo","family":"Sim","sequence":"additional","affiliation":[{"name":"Chemical Kinomics Research Center, Future Convergence Research Division, Korean Institute of Science and Technology, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and World Class University Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheol Soo","family":"Choi","sequence":"additional","affiliation":[{"name":"Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea"},{"name":"Gil Medical Center, Gachon University of Medicine and Science, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Bum","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Korea"},{"name":"Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul-Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hoi","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Korea University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hueng-Sik","family":"Choi","sequence":"additional","affiliation":[{"name":"National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea"},{"name":"Research Institute of Medical Sciences, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2013,8,15]]},"reference":[{"key":"2022031223132783500_B1","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.2337\/diacare.21.9.1414","article-title":"Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections","volume":"21","author":"King","year":"1998","journal-title":"Diabetes Care"},{"key":"2022031223132783500_B2","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2174\/157339906777950651","article-title":"Metformin beyond diabetes: new life for an old drug","volume":"2","author":"Rotella","year":"2006","journal-title":"Curr Diabetes Rev"},{"key":"2022031223132783500_B3","doi-asserted-by":"crossref","first-page":"22618","DOI":"10.1074\/jbc.274.32.22618","article-title":"Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3","volume":"274","author":"Hong","year":"1999","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.gene.2004.07.010","article-title":"Estrogen receptor-related receptor gamma has an exceptionally broad specificity of DNA sequence recognition","volume":"340","author":"Razzaque","year":"2004","journal-title":"Gene"},{"key":"2022031223132783500_B5","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1002\/pros.20429","article-title":"Molecular cloning and functional study of rat estrogen receptor-related receptor gamma in rat prostatic cells","volume":"66","author":"Lui","year":"2006","journal-title":"Prostate"},{"key":"2022031223132783500_B6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.mce.2006.11.002","article-title":"Interplay between estrogen-related receptor alpha (ERRalpha) and gamma (ERRgamma) on the regulation of ERRalpha gene expression","volume":"264","author":"Zhang","year":"2007","journal-title":"Mol Cell Endocrinol"},{"key":"2022031223132783500_B7","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1210\/er.2008-0017","article-title":"Transcriptional control of energy homeostasis by the estrogen-related receptors","volume":"29","author":"Gigu\u00e8re","year":"2008","journal-title":"Endocr Rev"},{"key":"2022031223132783500_B8","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/35093050","article-title":"Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1","volume":"413","author":"Yoon","year":"2001","journal-title":"Nature"},{"key":"2022031223132783500_B9","doi-asserted-by":"crossref","first-page":"306","DOI":"10.2337\/db07-0381","article-title":"Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP","volume":"57","author":"Kim","year":"2008","journal-title":"Diabetes"},{"key":"2022031223132783500_B10","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1164847","article-title":"Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke\u2019s disease","volume":"322","author":"Chopra","year":"2008","journal-title":"Science"},{"key":"2022031223132783500_B11","doi-asserted-by":"crossref","first-page":"28762","DOI":"10.1074\/jbc.M109.034165","article-title":"Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation","volume":"284","author":"Xie","year":"2009","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B12","doi-asserted-by":"crossref","first-page":"39897","DOI":"10.1074\/jbc.M608657200","article-title":"Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression","volume":"281","author":"Zhang","year":"2006","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B13","doi-asserted-by":"crossref","first-page":"21628","DOI":"10.1074\/jbc.M111.315168","article-title":"Orphan nuclear receptor estrogen-related receptor \u03b3 (ERR\u03b3) is key regulator of hepatic gluconeogenesis","volume":"287","author":"Kim","year":"2012","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B14","doi-asserted-by":"crossref","first-page":"38035","DOI":"10.1074\/jbc.M111.250613","article-title":"Estrogen-related receptor \u03b3 (ERR\u03b3) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling","volume":"286","author":"Kim","year":"2011","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B15","doi-asserted-by":"crossref","first-page":"8880","DOI":"10.1073\/pnas.151244398","article-title":"4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma","volume":"98","author":"Coward","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031223132783500_B16","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.bmcl.2005.11.030","article-title":"Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma","volume":"16","author":"Chao","year":"2006","journal-title":"Bioorg Med Chem Lett"},{"key":"2022031223132783500_B17","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1136\/gutjnl-2012-303347","article-title":"Estrogen-related receptor \u03b3 controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol","volume":"62","author":"Kim","year":"2013","journal-title":"Gut"},{"key":"2022031223132783500_B18","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nm1044","article-title":"PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3","volume":"10","author":"Koo","year":"2004","journal-title":"Nat Med"},{"key":"2022031223132783500_B19","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.cmet.2010.02.016","article-title":"Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH","volume":"11","author":"Lee","year":"2010","journal-title":"Cell Metab"},{"key":"2022031223132783500_B20","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.cmet.2009.01.007","article-title":"TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1","volume":"9","author":"Ryu","year":"2009","journal-title":"Cell Metab"},{"key":"2022031223132783500_B21","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1172\/JCI13579","article-title":"Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance","volume":"117","author":"Choi","year":"2007","journal-title":"J Clin Invest"},{"key":"2022031223132783500_B22","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.2337\/diabetes.53.suppl_3.S215","article-title":"The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes","volume":"53","author":"Winzell","year":"2004","journal-title":"Diabetes"},{"key":"2022031223132783500_B23","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1172\/JCI40671","article-title":"Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1\/AMPK pathway via a decrease in hepatic energy state","volume":"120","author":"Foretz","year":"2010","journal-title":"J Clin Invest"},{"key":"2022031223132783500_B24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.bbagrm.2008.08.012","article-title":"Modulation of adipogenesis-related gene expression by estrogen-related receptor gamma during adipocytic differentiation","volume":"1789","author":"Kubo","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"2022031223132783500_B25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1074\/jbc.M509276200","article-title":"Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription","volume":"281","author":"Herzog","year":"2006","journal-title":"J Biol Chem"},{"key":"2022031223132783500_B26","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1677\/jme.1.01586","article-title":"Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element","volume":"34","author":"Liu","year":"2005","journal-title":"J Mol Endocrinol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/62\/9\/3093\/571367\/3093.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/62\/9\/3093\/571367\/3093.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:32:55Z","timestamp":1667406775000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/62\/9\/3093\/34020\/Inverse-Agonist-of-Nuclear-Receptor-ERR-Mediates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,15]]},"references-count":26,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2013,8,15]]},"published-print":{"date-parts":[[2013,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db12-0946","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,8,15]]}}}