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

Weiwei Liu, Hao Zhou, Han Wang, Quanri Zhang, Renliang Zhang, Belinda Willard, Caini Liu, Zizhen Kang, Xiao Li () and Xiaoxia Li ()
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Weiwei Liu: Lerner Research Institute, Cleveland Clinic
Hao Zhou: Lerner Research Institute, Cleveland Clinic
Han Wang: Lerner Research Institute, Cleveland Clinic
Quanri Zhang: Lerner Research Institute, Cleveland Clinic
Renliang Zhang: Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic
Belinda Willard: Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic
Caini Liu: Lerner Research Institute, Cleveland Clinic
Zizhen Kang: Carver College of Medicine, University of Iowa
Xiao Li: Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University
Xiaoxia Li: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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-1β 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-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β 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.

Date: 2022
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DOI: 10.1038/s41467-022-30470-w

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