title: Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway.
abstract: The transcription factor nuclear factor-κB (NF-κB) mediates inflammation and stress signals in cells. To test NF-κB in the control of hepatic insulin sensitivity, we inactivated NF-κB in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-κB activity. NF-κB was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-α. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-κB inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.
authors.affiliation: Department of Gastroenterology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.
authors.forename: Bilun
authors.initials: B
authors.lastname: Ke
authors.affiliation: Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine in Henan Province, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Pulmonary Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Vincent
authors.initials: V
authors.lastname: Manganiello
authors.affiliation: Department of Gastroenterology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China yej@pbrc.edu wubin6@mail.sysu.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA yej@pbrc.edu wubin6@mail.sysu.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004734:Energy Metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D016328:NF-kappa B; D051996:Transcription Factor RelA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human