IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects

Nat Med. 2019 Apr;25(4):575-582. doi: 10.1038/s41591-019-0358-x. Epub 2019 Mar 4.

Abstract

Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / pharmacology
  • Anti-Obesity Agents / therapeutic use*
  • Diet
  • HEK293 Cells
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Leptin / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / drug therapy*
  • Receptors, Interleukin-1 Type I / metabolism*
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use*

Substances

  • Anti-Obesity Agents
  • Interleukin 1 Receptor Antagonist Protein
  • Leptin
  • Receptors, Interleukin-1 Type I
  • Triterpenes
  • celastrol