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

Feng, XD; Guan, DX; Auen, T; Choi, JW; Hernandez, MAS; Lee, J; Chun, H; Faruk, F; Kaplun, E; Herbert, Z; Copps, KD; Ozcan, U

Ozcan, U (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.

NATURE MEDICINE, 2019; 25 (4): 575


Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far(1). 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.

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