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-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.

• Authors: 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, Young-Myeong Kim
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 6303 (10 22 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 36272977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• NF-kappa B
• NF-KappaB Inhibitor alpha
• Cytokines
• Amino Acids

Topics

• Mice
• Animals
• NF-kappa B (metabolism)
• NF-KappaB Inhibitor alpha (genetics)
• Obesity (complications, genetics, metabolism)
• Inflammation (metabolism)
• Fatty Liver (metabolism)
• Cytokines
• Amino Acids