In:
Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-10-22)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-022-34110-1
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2022
detail.hit.zdb_id:
2553671-0
