Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice

Bing Han, Zhan-Ming Li, Xu-Yun Zhao, Kai Liang, Yu-Qin Mao, Shi-Long Zhang, Li-Ying Huang, Chao-Yue Kong, Xin Peng, Hui-Ling Chen, Jia-Ting Huang, Zhao-Xia Wu, Jin-Qing Yao, Pei-Ran Cai, Zheng-Yan Zhang, Xu-Min Zhang, Zhu-Jun Yao (), Guo-Qiang Chen () and Li-Shun Wang ()
Additional contact information
Bing Han: Fudan University
Zhan-Ming Li: Fudan University
Xu-Yun Zhao: Shanghai Jiao Tong University School of Medicine
Kai Liang: Peking University
Yu-Qin Mao: Fudan University
Shi-Long Zhang: Fudan University
Li-Ying Huang: Shanghai Jiao-Tong University School of Medicine
Chao-Yue Kong: Fudan University
Xin Peng: Shanghai Jiao Tong University School of Medicine
Hui-Ling Chen: Fudan University
Jia-Ting Huang: Fudan University
Zhao-Xia Wu: Fudan University
Jin-Qing Yao: Fudan University
Pei-Ran Cai: Fudan University
Zheng-Yan Zhang: Fudan University
Xu-Min Zhang: Fudan University
Zhu-Jun Yao: Nanjing University
Guo-Qiang Chen: Hainan Medical University
Li-Shun Wang: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005’s anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.

Date: 2024
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DOI: 10.1038/s41467-024-53118-3

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