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

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外文摘要：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 Ml-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.

外文关键词：

TBC1D1AMPKRab8aNOX2ROSinflammationmacrophageobesity

作者：

Qi Wang、Ping Rong、Wen Zhang、Xinyu Yang、Liang Chen、Ye Cao、Minjun Liu、Weikuan Feng、Qian Ouyang、Qiaoli Chen、Hailong Li、Hui Liang、Fanguo Meng、Hong-Yu Wang、Shuai Chen

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作者单位：

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

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

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

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

Department of General Surgery,First Affiliated Hospital,Nanjing Medical University,Nanjing 210029,China

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基金：

Ministry of Science and Technology of ChinaMinistry of Science and Technology of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central Universities

项目编号：

2018YFA08011002021YFF0702100320250193197071931971067021414380533021414380505

出版年：

2024

DOI：

10.1007/s11427-024-2628-1

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(9)