{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T06:57:20Z","timestamp":1760425040836},"reference-count":55,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,5,1]]},"abstract":"<jats:p>We have reported that the nuclear factor-\u03baB (NF-\u03baB) induces chronic inflammation in the adipose tissue of p65 transgenic (Tg) mice, in which the NF-\u03baB subunit p65 (RelA) is overexpressed from the adipocyte protein 2 (aP2) gene promoter. Tg mice suffer a mild lipodystrophy and exhibit deficiency in adipocyte differentiation. To understand molecular mechanism of the defect in adipocytes, we investigated glyceroneogenesis by examining the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in adipocytes. In aP2-p65 Tg mice, Pepck expression is inhibited at both the mRNA and protein levels in adipose tissue. The mRNA reduction is a consequence of transcriptional inhibition but not alteration in mRNA stability. The Pepck gene promoter is inhibited by NF-\u03baB, which enhances the corepressor activity through activation of histone deacetylase 3 (HDAC3) in the nucleus. HDAC3 suppresses Pepck transcription by inhibiting the transcriptional activators, peroxisome proliferator-activated receptor-\u03b3, and cAMP response element binding protein. The NF-\u03baB activity is abolished by Hdac3 knockdown or inhibition of HDAC3 catalytic activity. In a chromatin immunoprecipitation assay, HDAC3 interacts with peroxisome proliferator-activated receptor-\u03b3 and cAMP response element binding protein in the Pepck promoter when NF-\u03baB is activated by TNF-\u03b1. These results suggest that HDAC3 mediates NF-\u03baB activity to repress Pepck transcription. This mechanism is responsible for inhibition of glyceroneogenesis in adipocytes, which contributes to lipodystrophy in the aP2-p65 Tg mice.<\/jats:p>","DOI":"10.1210\/en.2010-0828","type":"journal-article","created":{"date-parts":[[2011,3,16]],"date-time":"2011-03-16T02:24:37Z","timestamp":1300242277000},"page":"1829-1838","source":"Crossref","is-referenced-by-count":24,"title":["Inhibition of Glyceroneogenesis by Histone Deacetylase 3 Contributes to Lipodystrophy in Mice with Adipose Tissue Inflammation"],"prefix":"10.1210","volume":"152","author":[{"given":"Jin","family":"Zhang","sequence":"first","affiliation":[{"name":"Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara M.","family":"Henagan","sequence":"first","affiliation":[{"name":"Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhanguo","family":"Gao","sequence":"first","affiliation":[{"name":"Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianping","family":"Ye","sequence":"first","affiliation":[{"name":"Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2011,3,15]]},"reference":[{"key":"2020071612432128900_B1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/ijo.2008.229","article-title":"Emerging role of adipose tissue hypoxia in obesity and insulin resistance.","volume":"33","author":"Ye","year":"2009","journal-title":"Int J Obes (Lond)"},{"key":"2020071612432128900_B2","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders.","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"2020071612432128900_B3","doi-asserted-by":"crossref","first-page":"E1118","DOI":"10.1152\/ajpendo.00435.2007","article-title":"Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob\/ob and dietary obese mice.","volume":"293","author":"Ye","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612432128900_B4","doi-asserted-by":"crossref","first-page":"E333","DOI":"10.1152\/ajpendo.90760.2008","article-title":"Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue.","volume":"296","author":"Yin","year":"2009","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612432128900_B5","doi-asserted-by":"crossref","first-page":"7405","DOI":"10.1128\/MCB.22.21.7405-7416.2002","article-title":"Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2\u03b1.","volume":"22","author":"Koumenis","year":"2002","journal-title":"Mol Cell Biol"},{"key":"2020071612432128900_B6","doi-asserted-by":"crossref","first-page":"901","DOI":"10.2337\/db06-0911","article-title":"Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.","volume":"56","author":"Hosogai","year":"2007","journal-title":"Diabetes"},{"key":"2020071612432128900_B7","doi-asserted-by":"crossref","first-page":"4637","DOI":"10.1074\/jbc.M109.068007","article-title":"Uncoupling of inflammation and insulin resistance by NF-\u03baB in transgenic mice through induction of energy expenditure.","volume":"285","author":"Tang","year":"2010","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B8","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1083\/jcb.108.3.1105","article-title":"Modulation of adipocyte differentiation by tumor necrosis factor and transforming growth factor \u03b2.","volume":"108","author":"Torti","year":"1989","journal-title":"J Cell Biol"},{"key":"2020071612432128900_B9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1172\/JCI115566","article-title":"Tumor necrosis factor-induced reversal of adipocytic phenotype of 3T3-L1 cells is preceded by a loss of nuclear CCAAT\/enhancer binding protein (C\/EBP).","volume":"89","author":"Ron","year":"1992","journal-title":"J Clin Invest"},{"key":"2020071612432128900_B10","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/oby.2005.74","article-title":"Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor \u03b1.","volume":"13","author":"Degawa-Yamauchi","year":"2005","journal-title":"Obes Res"},{"key":"2020071612432128900_B11","doi-asserted-by":"crossref","first-page":"re13","DOI":"10.1126\/stke.3572006re13","article-title":"Regulation and function of IKK and IKK-related kinases.","volume":"2006","author":"H\u00e4cker","year":"2006","journal-title":"Sci STKE"},{"key":"2020071612432128900_B12","doi-asserted-by":"crossref","first-page":"30413","DOI":"10.1074\/jbc.R300017200","article-title":"Glyceroneogenesis and the triglyceride\/fatty acid cycle.","volume":"278","author":"Reshef","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1073\/pnas.022616299","article-title":"A mutation in the peroxisome proliferator-activated receptor \u03b3-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice.","volume":"99","author":"Olswang","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612432128900_B14","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2337\/diabetes.55.02.06.db05-0482","article-title":"Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity.","volume":"55","author":"Franckhauser","year":"2006","journal-title":"Diabetes"},{"key":"2020071612432128900_B15","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2337\/diabetes.51.3.624","article-title":"Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance.","volume":"51","author":"Franckhauser","year":"2002","journal-title":"Diabetes"},{"key":"2020071612432128900_B16","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.2337\/diab.45.12.1661","article-title":"Thiazolidinediones in the treatment of insulin resistance and type II diabetes.","volume":"45","author":"Saltiel","year":"1996","journal-title":"Diabetes"},{"key":"2020071612432128900_B17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1146\/annurev.biochem.66.1.581","article-title":"Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression.","volume":"66","author":"Hanson","year":"1997","journal-title":"Annu Rev Biochem"},{"key":"2020071612432128900_B18","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/10409230590935479","article-title":"Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C.","volume":"40","author":"Chakravarty","year":"2005","journal-title":"Crit Rev Biochem Mol Biol"},{"key":"2020071612432128900_B19","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1128\/MCB.15.1.351","article-title":"PPAR\u03b32 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene.","volume":"15","author":"Tontonoz","year":"1995","journal-title":"Mol Cell Biol"},{"key":"2020071612432128900_B20","doi-asserted-by":"crossref","first-page":"E84","DOI":"10.1152\/ajpendo.00178.2006","article-title":"Inactivation of PKC\u03b8 leads to increased susceptibility to obesity and dietary insulin resistance in mice","volume":"292","author":"Gao","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612432128900_B21","doi-asserted-by":"crossref","first-page":"4540","DOI":"10.1074\/jbc.M507784200","article-title":"Regulation of nuclear translocation of HDAC3 by I\u03baB\u03b1 is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor \u03b3 function.","volume":"281","author":"Gao","year":"2006","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B22","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1210\/me.2007-0072","article-title":"Nuclear corepressor is required for inhibition of phosphoenolpyruvate carboxykinase expression by tumor necrosis factor-\u03b1.","volume":"21","author":"Yan","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612432128900_B23","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1210\/me.2003-0383","article-title":"Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.","volume":"18","author":"Gao","year":"2004","journal-title":"Mol Endocrinol"},{"key":"2020071612432128900_B24","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.2337\/db08-1637","article-title":"Butyrate improves insulin sensitivity and increases energy expenditure in mice.","volume":"58","author":"Gao","year":"2009","journal-title":"Diabetes"},{"key":"2020071612432128900_B25","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.biochi.2003.11.010","article-title":"Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes.","volume":"85","author":"Tordjman","year":"2003","journal-title":"Biochimie (Paris)"},{"key":"2020071612432128900_B26","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1210\/en.2006-1760","article-title":"Acute and selective inhibition of adipocyte glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase by interferon \u03b3.","volume":"148","author":"Khazen","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612432128900_B27","doi-asserted-by":"crossref","first-page":"21091","DOI":"10.1074\/jbc.M500754200","article-title":"Coactivators and corepressors of NF-\u03baB in I\u03baB\u03b1 gene promoter","volume":"280","author":"Gao","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B28","doi-asserted-by":"crossref","first-page":"4040","DOI":"10.1128\/IAI.60.10.4040-4050.1992","article-title":"Identification of tumor necrosis factor as a transcriptional regulator of the phosphoenolpyruvate carboxykinase gene following endotoxin treatment of mice.","volume":"60","author":"Hill","year":"1992","journal-title":"Infect Immun"},{"key":"2020071612432128900_B29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/00024382-199607000-00012","article-title":"Efficacy of anti-tumor necrosis factor polyclonal antibody on phosphoenolpyruvate carboxykinase expression in septic and endotoxemic rats.","volume":"6","author":"Chang","year":"1996","journal-title":"Shock"},{"key":"2020071612432128900_B30","doi-asserted-by":"crossref","first-page":"8509","DOI":"10.1016\/S0021-9258(18)43526-0","article-title":"Regulation of phosphoenolpyruvate carboxykinase (GTP) mRNA turnover in rat liver.","volume":"255","author":"Nelson","year":"1980","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/35093131","article-title":"CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.","volume":"413","author":"Herzig","year":"2001","journal-title":"Nature"},{"key":"2020071612432128900_B32","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":"2020071612432128900_B33","doi-asserted-by":"crossref","first-page":"27042","DOI":"10.1074\/jbc.M109.047340","article-title":"Activation of SIRT1 by resveratrol represses transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) by deacetylating hepatic nuclear factor 4\u03b1.","volume":"284","author":"Yang","year":"2009","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B34","doi-asserted-by":"crossref","first-page":"9447","DOI":"10.1074\/jbc.M105993200","article-title":"Functional domains of histone deacetylase-3.","volume":"277","author":"Yang","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B35","doi-asserted-by":"crossref","first-page":"6091","DOI":"10.1128\/MCB.21.18.6091-6101.2001","article-title":"The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.","volume":"21","author":"Guenther","year":"2001","journal-title":"Mol Cell Biol"},{"key":"2020071612432128900_B36","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1093\/emboj\/19.16.4342","article-title":"Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3.","volume":"19","author":"Li","year":"2000","journal-title":"EMBO J"},{"key":"2020071612432128900_B37","doi-asserted-by":"crossref","first-page":"7202","DOI":"10.1073\/pnas.97.13.7202","article-title":"The histone deacetylase-3 complex contains nuclear receptor corepressors.","volume":"97","author":"Wen","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612432128900_B38","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1074\/jbc.X400009200","article-title":"Metabolism in the era of molecular biology.","volume":"280","author":"Hanson","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B39","doi-asserted-by":"crossref","first-page":"9657","DOI":"10.1016\/S0021-9258(18)60581-2","article-title":"Identification of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase (GTP) gene.","volume":"264","author":"Roesler","year":"1989","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B40","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/89076","article-title":"Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.","volume":"7","author":"Makowski","year":"2001","journal-title":"Nat Med"},{"key":"2020071612432128900_B41","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1172\/JCI24767","article-title":"The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation.","volume":"116","author":"Shum","year":"2006","journal-title":"J Clin Invest"},{"key":"2020071612432128900_B42","doi-asserted-by":"crossref","first-page":"27031","DOI":"10.1074\/jbc.R109.040535","article-title":"Aspects of the control of phosphoenolpyruvate carboxykinase gene transcription.","volume":"284","author":"Yang","year":"2009","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B43","doi-asserted-by":"crossref","first-page":"32234","DOI":"10.1074\/jbc.M204873200","article-title":"Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter.","volume":"277","author":"Duong","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B44","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/nature03967","article-title":"The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.","volume":"437","author":"Koo","year":"2005","journal-title":"Nature"},{"key":"2020071612432128900_B45","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/nature08111","article-title":"The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis.","volume":"460","author":"Wang","year":"2009","journal-title":"Nature"},{"key":"2020071612432128900_B46","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1126\/science.1151363","article-title":"Hepatic glucose sensing via the CREB coactivator CRTC2.","volume":"319","author":"Dentin","year":"2008","journal-title":"Science"},{"key":"2020071612432128900_B47","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1172\/JCI35847","article-title":"Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice.","volume":"118","author":"Montgomery","year":"2008","journal-title":"J Clin Invest"},{"key":"2020071612432128900_B48","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.molcel.2008.02.030","article-title":"Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control.","volume":"30","author":"Bhaskara","year":"2008","journal-title":"Mol Cell"},{"key":"2020071612432128900_B49","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/emboj.2008.51","article-title":"Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks.","volume":"27","author":"Knutson","year":"2008","journal-title":"EMBO J"},{"key":"2020071612432128900_B50","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.molcel.2007.01.005","article-title":"c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis.","volume":"25","author":"Xia","year":"2007","journal-title":"Mol Cell"},{"key":"2020071612432128900_B51","doi-asserted-by":"crossref","first-page":"3686","DOI":"10.1093\/emboj\/cdg364","article-title":"JNK phosphorylation relieves HDAC3-dependent suppression of the transcriptional activity of c-Jun.","volume":"22","author":"Weiss","year":"2003","journal-title":"EMBO J"},{"key":"2020071612432128900_B52","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1128\/MCB.00882-06","article-title":"Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.","volume":"27","author":"Gr\u00e9goire","year":"2007","journal-title":"Mol Cell Biol"},{"key":"2020071612432128900_B53","doi-asserted-by":"crossref","first-page":"5122","DOI":"10.1128\/MCB.23.15.5122-5131.2003","article-title":"The N-CoR\/histone deacetylase 3 complex is required for repression by thyroid hormone receptor.","volume":"23","author":"Ishizuka","year":"2003","journal-title":"Mol Cell Biol"},{"key":"2020071612432128900_B54","doi-asserted-by":"crossref","first-page":"30358","DOI":"10.1074\/jbc.M401359200","article-title":"Requirement of histone deacetylase activity for signaling by STAT1.","volume":"279","author":"Klampfer","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071612432128900_B55","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.bbrc.2008.07.068","article-title":"Regulation of PPAR\u03b3 function by TNF-\u03b1.","volume":"374","author":"Ye","year":"2008","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/5\/1829\/9036008\/endo1829.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/5\/1829\/9036008\/endo1829.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,20]],"date-time":"2021-11-20T10:40:46Z","timestamp":1637404846000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/152\/5\/1829\/2457093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,3,15]]},"references-count":55,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2010-0828","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3,15]]}}}