Fig. 7: The Ucp1-mediated thermogenic pathway contributes to the anti-obesity effect of AA005. | Nature Communications

Fig. 7: The Ucp1-mediated thermogenic pathway contributes to the anti-obesity effect of AA005.

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

Fig. 7

a PCR confirmation of Ucp1 allele deletion in Ucp1−/− mice. Three different biological replicates were tested. b Weight gain recorded over 20 weeks in male littermates fed HFD with or without AA005 treatment in Ucp1−/− mice (n = 6 for vehicle-treated Ucp1−/− mice, n = 7 for AA005-treated Ucp1−/− mice for each group). c Representative photograph of vehicle- or AA005-treated Ucp1−/− mice fed HFD at experimental endpoint. Scale bar, 1 cm. d The average food intake of each mouse for 1 week was recorded (n = 6 for vehicle-treated mice, n = 7 for AA005-treated mice). e Fat and lean mass were recorded after 20 weeks treatment (n = 6 for vehicle-treated mice, n = 7 for AA005-treated mice). f Fat weight of iWAT, asWAT, eWAT, rWAT, mWAT, and BAT in Ucp1−/− mice treated with vehicle or AA005 (n = 6 for vehicle-treated mice, n = 7 for AA005-treated mice). Glucose tolerance test (GTT) (g), area under the curve (AUC) of GTT (h), insulin tolerance test (ITT) (i), and AUC of ITT (j) in vehicle and AA005-treated Ucp1−/− mice fed HFD (n = 6 for vehicle-treated mice, n = 7 for AA005-treated mice). k Representative images of haematoxylin and eosin (H&E) stained of iWAT, eWAT, and BAT. iWAT, n = 107 (Vehicle) and 114 (AA005) adipocytes per; eWAT, n = 115 (Vehicle) and 108 (AA005) adipocytes per group; BAT, n = 473 (Vehicle) and 474 (AA005) LDs per group. Scale bar, 50 μm. l AA005 targets HADHA to counteract obesity by inhibiting cardiolipin maturation and enhancing Ucp1-mediated thermogenesis pathway. AA005 demonstrates the ability to induce a brown-like transformation in adipose tissue and enhance energy expenditure in obese mice, thereby potentially exerting a pharmacological effect in combating obesity and improving glucose metabolism. Mechanistically, AA005 selectively enters adipocyte mitochondria and targets the binding site on HADHA, leading to inhibition of cardiolipin maturation in mitochondria. Consequently, AA005 alters the expression profile of cardiolipin. Notably, the presence of immature cardiolipin activates the Ucp1-mediated thermogenic pathway, consequently promoting mitochondrial thermogenesis. Data are presented as mean ± SEM. Unpaired, two-tailed Student’s t test. NS indicates not significant. Source data are provided as a Source Data file.

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