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

• Published in: Nature communications 2024-10, Vol.15 (1), p.9100-17, Article 9100
• Main Authors: Han, Bing, Li, Zhan-Ming, Zhao, Xu-Yun, Liang, Kai, Mao, Yu-Qin, Zhang, Shi-Long, Huang, Li-Ying, Kong, Chao-Yue, Peng, Xin, Chen, Hui-Ling, Huang, Jia-Ting, Wu, Zhao-Xia, Yao, Jin-Qing, Cai, Pei-Ran, Zhang, Zheng-Yan, Zhang, Xu-Min, Yao, Zhu-Jun, Chen, Guo-Qiang, Wang, Li-Shun
• Format: Article
• Language: English
• Subjects: 13/1; 13/89; 45/91; 631/154/436/2388; 631/154/555; 631/92/555; 692/699/2743/393; 82/80; Acetogenins - chemistry; Acetogenins - pharmacology; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Anti-Obesity Agents - chemistry; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Body fat; Body temperature; Diet; Diet, High-Fat; Energy expenditure; Energy Metabolism - drug effects; Health risk assessment; Health risks; Health services; High fat diet; High protein diet; Humanities and Social Sciences; Humans; Leptin; Leptin - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Trifunctional Protein, alpha Subunit - genetics; Mitochondrial Trifunctional Protein, alpha Subunit - metabolism; multidisciplinary; Nutrient deficiency; Obesity; Obesity - drug therapy; Obesity - genetics; Obesity - metabolism; Pharmacokinetics; Proteins; Proteomics; Science; Science (multidisciplinary); Thermogenesis; Thermogenesis - drug effects; Thermogenesis - genetics; Uncoupling protein 1; Uncoupling Protein 1 - genetics; Uncoupling Protein 1 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53118-3

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. Obesity is a significant health risk, and current treatments are inadequate. This study reveals that AA005, an annonaceous acetogenin mimic, targets mitochondrial HADHA in adipose tissue to boost thermogenesis via the UCP1 pathway, providing a promising new strategy for obesity treatment.