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^219/220Ala, 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.

在发育和 DNA 损伤反应 1 (REDD1) 表达中受到调节以应对代谢失衡和肥胖。然而，其在肥胖相关并发症中的作用尚不清楚。在这里，我们证明 REDD1–NF-κB 轴对于代谢性炎症和失调至关重要。全身或脂肪细胞缺乏Redd1的小鼠表现出限制性饮食诱导的肥胖、炎症、胰岛素抵抗和肝脂肪变性。骨髓Redd1缺陷小鼠显示出相似的结果，没有限制性肥胖和肝脂肪变性。雷德1- 缺乏脂肪来源的干细胞失去了分化成脂肪细胞的潜力；然而，REDD1 过表达通过从 NF-κB/IκBα 复合物中隔离 IκBα，通过非典型 IKK 非依赖性 NF-κB 激活刺激前脂肪细胞分化和促炎细胞因子表达。具有突变的 Lys ^219/220 Ala（IκBα 结合的关键氨基酸残基）的 REDD1 不能在体外刺激 NF-κB 激活、脂肪生成和炎症，并防止敲入小鼠的肥胖相关表型。REDD1-非典型 NF-κB 激活轴是肥胖、炎症和代谢并发症的治疗靶点。