Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1

Diabetes. 2018 Nov;67(11):2456-2465. doi: 10.2337/db18-0146. Epub 2018 Aug 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Eating / drug effects*
  • Energy Metabolism / drug effects
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism*
  • Plant Extracts / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Triterpenes / pharmacology*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism*
  • Weight Loss / drug effects*

Substances

  • Plant Extracts
  • Triterpenes
  • Uncoupling Protein 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • celastrol