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

Area of Science:

• Metabolism
• Molecular Biology
• Cell Signaling

Background:

• Nuclear factor-κB (NF-κB) is a key transcription factor regulating inflammatory and stress responses.
• Hepatic insulin sensitivity is crucial for glucose homeostasis and is often impaired in metabolic diseases.

Purpose of the Study:

• To investigate the role of NF-κB in the regulation of hepatic insulin sensitivity.
• To determine the molecular mechanisms by which NF-κB influences insulin signaling in the liver.

Main Methods:

• Generation of liver-specific NF-κB knockout (L-p65-KO) mice by crossing floxed-p65 and Alb-cre mice.
• Assessment of systemic and hepatic insulin sensitivity using high-fat diet (HFD) models, pyruvate tolerance tests, and Western blotting for Akt phosphorylation.
• Analysis of gene expression, intracellular cAMP levels, and cyclic nucleotide phosphodiesterase-3B (PDE3B) activity in liver tissues.

Main Results:

• L-p65-KO mice on HFD showed improved systemic insulin sensitivity and enhanced hepatic insulin sensitivity, evidenced by increased pyruvate tolerance and Akt phosphorylation.
• NF-κB inactivation led to decreased gluconeogenic gene expression and reduced intracellular cAMP levels in the liver.
• Absence of NF-κB activity increased PDE3B mRNA and protein levels, suggesting NF-κB normally suppresses PDE3B transcription.
• NF-κB was identified to inhibit PDE3B transcription via DNA-binding sites in its promoter in response to tumor necrosis factor-α.

Conclusions:

• NF-κB directly inhibits hepatic insulin sensitivity by upregulating intracellular cAMP levels through suppression of PDE3B gene transcription.
• Targeting the NF-κB/PDE3B pathway may offer a therapeutic strategy for improving hepatic insulin resistance.