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Celastrol-induced weight loss is driven by hypophagia and independent from UCP1.

Diabetes 67, 2456-2465 (2018)
Postprint Research data DOI
Open Access Green
as soon as is submitted to ZB.
Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep(ob) mice respond with a decrease in food intake and body weight, adult Lep(db) and Lep(ob) mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Tyrosine-phosphatase 1b; Induced Obese Mice; Insulin Sensitivity; Heat-shock; Activation; Fat; Inhibition; Leptin; Diet; Hsp90-cdc37
Reviewing status