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Inactivation of NF-?B p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway.


ABSTRACT: The transcription factor nuclear factor-?B (NF-?B) mediates inflammation and stress signals in cells. To test NF-?B in the control of hepatic insulin sensitivity, we inactivated NF-?B 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-?B activity. NF-?B was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-?. 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-?B inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.

SUBMITTER: Ke B 

PROVIDER: S-EPMC4587638 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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