Somatic ablation of IKKβ in liver and leukocytes is not tolerated in obese mice but hepatic IKKβ deletion improves fatty liver and insulin sensitivity

Abstract

The kinase IKKβ controls pro-inflammatory gene expression, and its activity in the liver and leukocytes was shown to drive metabolic inflammation and insulin resistance in obesity. However, it was also proposed that liver IKKβ signaling protects obese mice from insulin resistance and endoplasmic reticulum (ER) stress by increasing XBP1s protein stability. Furthermore, mice lacking IKKβ in leukocytes display increased lethality to lipopolysaccharides. This study aims at improving our understanding of the role of IKKβ signaling in obesity. We induced IKKβ deletion in hematopoietic cells and liver of obese mice by Cre-LoxP recombination, using an INF-inducible system, or a liver-specific IKKβ deletion in obese mice by adenovirus delivery of the Cre recombinase. The histopathological, immune, and metabolic phenotype of the mice was characterized. IKKβ deletion in the liver and hematopoietic cells was not tolerated in mice with established obesity exposed to the TLR3 agonist poly(I:C) and exacerbated liver damage and ER-stress despite elevated XBP1s. By contrast, liver-specific ablation of IKKβ in obese mice reduced steatosis and improved insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of denovo lipogenesis genes. We conclude that IKKβ blockage in liver and leukocytes

Tubular IKKβ Deletion Alleviates Acute Ischemic Kidney Injury and Facilitates Tissue Regeneration

“…Breeding and genotyping were performed according to standard procedures. IKKβ fl/fl mice [ 36 ] have been and were crossed with Pax8-rt-TA-LC1 Cre mice [ 37 ]. For the induction of tubular knockout of IKKβ, 6 weeks old IKKβ fl/fl (termed control) and Pax8-rt-TA-LC1 Cre /IKKβ fl/fl (termed IKKβ ∆Tub ) received 0.2 mg/mL doxycycline (Sigma Aldrich, Taufkirchen, Germany) in the drinking water for two weeks followed by one week wash out.…”