Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice
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.
Authors
- Xin Peng (ORCID: https://orcid.org/0000-0002-3665-8838)
- Xu-Yun Zhao
- Zhengyan Zhang (ORCID: https://orcid.org/0000-0002-4906-4481)
- Zhaoxia Wu (ORCID: https://orcid.org/0000-0001-6230-7452)
- Zhanming Li (ORCID: https://orcid.org/0000-0003-0872-3310)
- Li‐Shun Wang (ORCID: https://orcid.org/0000-0003-3972-683X)
- Zhu‐Jun Yao (ORCID: https://orcid.org/0000-0002-6716-4232)
- Bing Han (ORCID: https://orcid.org/0000-0001-7559-434X)
- Pei‐Ran Cai (ORCID: https://orcid.org/0000-0003-1319-4222)
- Yuqin Mao (ORCID: https://orcid.org/0000-0001-6863-354X)
- Chao‐Yue Kong
- Jiating Huang (ORCID: https://orcid.org/0000-0001-9306-2697)
- Shilong Zhang (ORCID: https://orcid.org/0000-0003-3095-4246)
- Hui‐Ling Chen (ORCID: https://orcid.org/0000-0002-2572-0595)
- Xumin Zhang (ORCID: https://orcid.org/0000-0002-2810-6363)
- Kai Liang (ORCID: https://orcid.org/0000-0002-9949-5044)
- Liying Huang
- Jin-Qing Yao
- Guoqiang Chen (ORCID: https://orcid.org/0000-0003-4936-2363)
Institutions
- Shanghai Jiao Tong University (CN)
- Peking University (CN)
- Fudan University (CN)
- Renji Hospital (CN)
- Minhang District Central Hospital (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- State Key Laboratory of Genetic Engineering
- Hainan Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1038/s41467-024-53118-3
- Citations
- 4
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.31
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- State Key Laboratory of Genetic Engineering