Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice.
Animals
Obesity
/ drug therapy
Male
Acetogenins
/ pharmacology
Diet, High-Fat
Mice
Thermogenesis
/ drug effects
Uncoupling Protein 1
/ metabolism
Mitochondria
/ metabolism
Energy Metabolism
/ drug effects
Mice, Inbred C57BL
Mitochondrial Trifunctional Protein, alpha Subunit
/ metabolism
Anti-Obesity Agents
/ pharmacology
Adipose Tissue
/ metabolism
Leptin
/ metabolism
Mice, Knockout
Humans
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
30
09
2023
accepted:
27
09
2024
medline:
23
10
2024
pubmed:
23
10
2024
entrez:
22
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39438446
doi: 10.1038/s41467-024-53118-3
pii: 10.1038/s41467-024-53118-3
doi:
Substances chimiques
Acetogenins
0
Uncoupling Protein 1
0
Mitochondrial Trifunctional Protein, alpha Subunit
EC 1.1.1.211
Anti-Obesity Agents
0
Leptin
0
Ucp1 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9100Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81803601
Informations de copyright
© 2024. The Author(s).
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