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Obese skeletal muscle-expressed interferon regulatory factor 4 transcriptionally regulates mitochondrial branched-chain aminotransferase reprogramming metabolome

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posted on 17.06.2022, 15:33 authored by Ting Yao, Hongmei Yan, Xiaopeng Zhu, Qiongyue Zhang, Xingyu Kong, Shanshan Guo, Yonghao Feng, Hui Wang, Yinghui Hua, Jing Zhang, Steven D. Mittelman, Peter Tontonoz, Zhenqi Zhou, Tiemin Liu, Xingxing Kong

  

In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle were not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species (human and mouse), and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated that IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of the high-fat diet (HFD), increased branched-chain amino acids (BCAAs) level of serum and muscle, and re-programmed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAAs and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity (DIO).

Funding

This work was funded by the National Natural Science Foundation of China (92157203), NIH R00 DK106550 to X.K., the National Key R&D Program of China (2019YFA0801900, 2018YFA0800300), the National Natural Science Foundation of China (31971074, 32150610475) to T.L., the National Natural Science Foundation of China (82100849) and Young Foundation of Zhongshan Hospital Fudan University (2021ZSQN07) to X.Z., American Heart Association (AHA) Postdoctoral Fellowship (18POST34060000) to T.Y., Natural Science Foundation of Shanghai Science and Technology Commission, General project (21ZR1413200) to H.Y..

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