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

Dong-Keon Lee, Taesam Kim, Junyoung Byeon, Minsik Park, Suji Kim, Joohwan Kim, Seunghwan Choi, Gihwan Lee, Chanin Park, Keun Woo Lee, Yong Jung Kwon, Jeong-Hyung Lee, Young-Guen Kwon and Young-Myeong Kim ()
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Dong-Keon Lee: Kangwon National University
Taesam Kim: Kangwon National University
Junyoung Byeon: Kangwon National University
Minsik Park: Kangwon National University
Suji Kim: Kangwon National University
Joohwan Kim: Kangwon National University
Seunghwan Choi: Kangwon National University
Gihwan Lee: Gyeongsang National University
Chanin Park: Gyeongsang National University
Keun Woo Lee: Gyeongsang National University
Yong Jung Kwon: GILO Foundation
Jeong-Hyung Lee: Kangwon National University
Young-Guen Kwon: Yonsei University
Young-Myeong Kim: Kangwon National University

Nature Communications, 2022, vol. 13, issue 1, 1-16

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 Lys219/220Ala, 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.

Date: 2022
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DOI: 10.1038/s41467-022-34110-1

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