IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice

Toll-like receptors/Interleukin-1 receptor signaling plays an important role in high-fat diet-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduces high-fat diet-induced body weight gain, increases whole body energy expenditure and improves insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1 beta stimulation induces the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1 beta-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1 beta induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuates high-fat diet-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a potential therapeutic target for obesity. TLRs/IL-1R signaling play a role in high-fat diet induced adipose tissue dysfunction and obesity-associated metabolic syndrome. Here the authors report that adipocyte-specific deficiency of IL-1 Receptor-Associated Kinase M (IRAKM) ameliorates diet induced obesity, potentially via the mitochondrial citrate carrier Slc25a1 and reduced de novo lipogenesis.

Automated summary

The Toll-like receptors/Interleukin-1 receptor signaling pathway has been found to play an important role in adipose tissue dysfunction and obesity-associated metabolic syndromes caused by high-fat diet. In this study, the authors discovered an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that promotes diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduced weight gain, increased energy expenditure, improved insulin resistance, and decreased lipid accumulation and adipocyte cell sizes. The authors also found that IL-1 beta stimulation induced the translocation of IRAKM Myddosome to mitochondria, promoting de novo lipogenesis in adipocytes. Moreover, the IRAKM-Slc25a1 axis mediated IL-1 beta induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. The inactivation of IRAKM kinase also attenuated high-fat diet-induced obesity. These findings highlight the tight connection between inflammation and adipocyte metabolism and suggest a potential therapeutic target for obesity.