REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation

Abstract

Regulated in development and DNA damage response 1 (REDD1) expression is upregulated in response to metabolic imbalance and obesity. However, its role in obesity-associated complications is unclear. Here, we demonstrate that the REDD1-NF-kappa B axis is crucial for metabolic inflammation and dysregulation. Mice lacking Redd1 in the whole body or adipocytes exhibited restrained diet-induced obesity, inflammation, insulin resistance, and hepatic steatosis. Myeloid Redd1-deficient mice showed similar results, without restrained obesity and hepatic steatosis. Redd1-deficient adipose-derived stem cells lost their potential to differentiate into adipocytes; however, REDD1 overexpression stimulated preadipocyte differentiation and proinflammatory cytokine expression through atypical IKK-independent NF-kappa B activation by sequestering I kappa B alpha from the NF-kappa B/I kappa B alpha complex. REDD1 with mutated Lys(219/220)Ala, key amino acid residues for I kappa B alpha binding, could not stimulate NF-kappa B activation, adipogenesis, and inflammation in vitro and prevented obesity-related phenotypes in knock-in mice. The REDD1-atypical NF-kappa B activation axis is a therapeutic target for obesity, meta-inflammation, and metabolic complications. The stress response protein REDD1 is regulates inflammation and energy metabolism. Here the authors report that global or adipocyte-specific deletion of REDD1 inhibits diet induced obesity, insulin resistance, liver steatosis and inflammation in mice, at least in part via reduced atypical NF-kappa B activation.