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TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity

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Abstract

Energy status is linked to the production of reactive oxygen species (ROS) in macrophages, which is elevated in obesity. However, it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity. Here, we show that the Rab-GTPase activating protein (RabGAP) TBC1D1, a substrate of the energy sensor AMP-activated protein kinase (AMPK), is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development. TBC1D1 deletion decreases, whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231A mutation increases, ROS production and M1-like polarization in macrophages. Mechanistically, TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation. Transplantation of TBC1D1S231A bone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable TtSOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231A mutation- and diet-induced obesity. Our findings therefore have implications for drug discovery to combat obesity.

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Acknowledgement

We thank members of the resource unit at Nan**g University for technical assistance. Thanks to the Ministry of Science and Technology of China (Grant Nos. 2018YFA0801100 and 2021YFF0702100), the National Natural Science Foundation of China (Grant Nos. 32025019 and 31970719 to S.C., 31971067), and the Fundamental Research Funds for the Central Universities (021414380533, 021414380505) for financial support.

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  1. Contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nan**g Drum Tower Hospital, The Affiliated Hospital of Nan**g University Medical School, Model Animal Research Center, School of Medicine, Nan**g University, Nan**g, 210061, China

    Qi Wang, ** Rong, Wen Zhang, **nyu Yang, Ye Cao, Minjun Liu, Weikuan Feng, Qian Ouyang, Qiaoli Chen, Hong-Yu Wang & Shuai Chen

  2. MOE Key Laboratory of Model Animal for Disease Study, Department of Endocrinology, Nan**g Drum Tower Hospital, The Affiliated Hospital of Nan**g University Medical School, Model Animal Research Center, School of Medicine, Nan**g University, Nan**g, 210061, China

    Qi Wang, ** Rong, Wen Zhang, **nyu Yang, Ye Cao, Minjun Liu, Weikuan Feng, Qian Ouyang, Qiaoli Chen, Hong-Yu Wang & Shuai Chen

  3. College of Life Science, Anhui Medical University, Hefei, 230032, China

    Liang Chen

  4. Redox Medical Center for Public Health, Medical College of Soochow University, Suzhou, 215123, China

    Hailong Li & Fanguo Meng

  5. Department of General Surgery, First Affiliated Hospital, Nan**g Medical University, Nan**g, 210029, China

    Hui Liang

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  1. Qi Wang
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Correspondence to Hong-Yu Wang or Shuai Chen.

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Wang, Q., Rong, P., Zhang, W. et al. TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-024-2628-1

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