Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme a subunit to treat obesity

Abstract

Obesity and related disease is a serious threat to people's health. However, currently available anti-obesity drugs couldn’t fully meet the clinic needs. We found annonaceous acetogenin mimic AA005 treatment could resist obesity in diet-induced obese mice and leptin-deficient (ob/ob) mice at non-cytotoxic dose. Then, with a bait of biotin labeled AA005, 44 proteins were captured as AA005 binding proteins using chemical proteomics. Alpha subunit of mitochondrial trifunctional protein (HADHA) showed the strongest affinity and its knockdown suppressed the fat accumulation in 3T3-L1 cells, identical to the effect of AA005. Pharmacokinetic analysis indicated that AA005 were mainly distributed in liver and fat tissue, and thus we constructed tissue-specific HADHA knockout mice of liver and fat. The obesities induced by high fat diet in these mice were significantly inhibited. Intriguingly, elevating energy expenditure and activated thermogenesis pathway were detected in AA005-treated as well as HADHA knockout mice. Thus, AA005 targeting HADHA may serve as novel therapeutic strategy for obesity.