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

Area of Science:

• Molecular Biology
• Metabolic Disease Research
• Immunology

Background:

• Regulated in development and DNA damage response 1 (REDD1) is upregulated with metabolic imbalance and obesity.
• The specific role of REDD1 in obesity-associated complications remains largely undefined.

Purpose of the Study:

• To elucidate the role of the REDD1-NF-κB signaling axis in metabolic inflammation and dysregulation associated with obesity.
• To investigate REDD1 as a potential therapeutic target for obesity and its complications.

Main Methods:

• Utilized whole-body and cell-specific Redd1 knockout mouse models (adipocyte, myeloid).
• Examined REDD1's effect on adipocyte differentiation and inflammatory cytokine production in vitro.
• Investigated the mechanism of NF-κB activation by REDD1, including IκBα sequestration and atypical IKK-independent pathways.
• Employed knock-in mice with mutated REDD1 (Lys219/220Ala) to assess the importance of IκBα binding.

Main Results:

• Mice lacking Redd1 exhibited reduced diet-induced obesity, inflammation, insulin resistance, and hepatic steatosis.
• Myeloid-specific Redd1 deficiency showed similar metabolic benefits but without significant obesity restraint.
• Redd1 deficiency impaired adipocyte differentiation, while REDD1 overexpression promoted it and inflammatory cytokine release via atypical NF-κB activation.
• Mutations in REDD1 affecting IκBα binding abolished its ability to activate NF-κB, promote adipogenesis, and induce inflammation, and prevented obesity-related phenotypes in mice.

Conclusions:

• The REDD1-NF-κB axis is critical for driving metabolic inflammation and dysregulation in obesity.
• Targeting the REDD1-mediated atypical NF-κB activation pathway presents a promising therapeutic strategy for obesity, meta-inflammation, and associated metabolic complications.