REDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation
Dong‐Keon Lee, Taesam Kim, Junyoung Byeon, Minsik Park, Suji Kim, Joo‐Hwan Kim, Seunghwan Choi, Gihwan Lee, Chanin Park, Keun Woo Lee, Yong Jung Kwon, Jeong‐Hyung Lee, Young‐Guen Kwon, Young‐Myeong Kim
Abstract
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-κB 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-κB activation by sequestering IκBα from the NF-κB/IκBα complex. REDD1 with mutated Lys 219/220 Ala, key amino acid residues for IκBα binding, could not stimulate NF-κB activation, adipogenesis, and inflammation in vitro and prevented obesity-related phenotypes in knock-in mice. The REDD1-atypical NF-κB activation axis is a therapeutic target for obesity, meta-inflammation, and metabolic complications.