Celastrol prevents high‐fat diet‐induced obesity by promoting white adipose tissue browning

Dear Editor, Despite advances in therapy for obesity, effective therapeutic strategies for weight loss are still needed.1 Our team revealed that celastrol promoted white adipose tissue (WAT) browning, and protected against high-fat diet (HFD)-induced obesity via activation of hypothalamus sympathetic nervous system β3AR axis. Fatty acid transport 2 (Fatp2) may serve as an important factor to mediate the browning-inducing effects of celastrol. This study may provide a basis for exploring a new strategy for the treatment of obesity. Celastrol is a leptin sensitizer.2 We found that long-term treatment with celastrol at doses of 10 and 1 μg/kg prevented the development of obesity (Figure S1A,B). Food intake was suppressed by celastrol at dosages of 1000, 100 and 10 μg/kg, but not 1 μg/kg (Figure S1C,D). Celastrol treatment at doses of 1000 and 100 μg/kg resulted in a severe decline in food intake and body weight in HFDfed mice by 4–5 days (Figure S1A–C). Increased UCP1 expression was observed in inguinal WAT (iWAT) of the mice treated with celastrol at a dose of 1 μg/kg (Figure S1E). The canonical molecular and morphological characteristics of WAT browning including the increased protein levels of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor-UCP1 and PGC1γ coactivator 1-α (PGC1α), and the decreased size of multilocular adipocytes were also seen in iWAT (Figure S1F–H). The increased expressions of WAT browning-associated genes were not seen in mice treated with celastrol at a dose of .1 μg/kg (Figure S1I). The HFD-induced obesity was prevented by celastrol at the dose of 1 μg/kg during a 3-month treatment without affecting food intake (Figure 1A–E). A sustained expression of WAT browningassociated genes was observed in iWAT of celastrol-treated mice (Figure 1F). Celastrol diminished the increment of adiposity in both room temperature (RT) and thermoneutrality (Figure 1G–I,K). No significant difference in the food intake was found (Figure 1J). Celastrol stimulated expressions of WAT browning-associated genes in iWAT at