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.

journal_name

Diabetes

journal_title

Diabetes

authors

Ke B,Zhao Z,Ye X,Gao Z,Manganiello V,Wu B,Ye J

doi

10.2337/db15-0242

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

3355-62

issue

10

eissn

0012-1797

issn

1939-327X

pii

db15-0242

journal_volume

64

pub_type

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