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

Xudong Feng; Dongxian Guan; Thomas Auen; Jae Won Choi; Mario Andrés Salazar Hernández; Jaemin Lee; Hyonho Chun; Farhana Faruk; Esther Kaplun; Zachary Herbert; Kyle D. Copps; Umut Ozcan

doi:10.1038/s41591-019-0358-x

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

Xudong Feng, Dongxian Guan, Thomas Auen, Jae Won Choi, Mario Andrés Salazar Hernández, Jaemin Lee, Hyonho Chun, Farhana Faruk, Esther Kaplun, Zachary Herbert, Kyle D. Copps, Umut Ozcan

Department of New Biology

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

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.

Original language	English
Pages (from-to)	575-582
Number of pages	8
Journal	Nature Medicine
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41591-019-0358-x
State	Published - 1 Apr 2019

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© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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title = "IL1R1 is required for celastrol{\textquoteright}s leptin-sensitization and antiobesity effects",

abstract = "Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol{\textquoteright}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{\textquoteright}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{\textquoteright}s metabolic actions.",

author = "Xudong Feng and Dongxian Guan and Thomas Auen and Choi, {Jae Won} and {Salazar Hern{\'a}ndez}, {Mario Andr{\'e}s} and Jaemin Lee and Hyonho Chun and Farhana Faruk and Esther Kaplun and Zachary Herbert and Copps, {Kyle D.} and Umut Ozcan",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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doi = "10.1038/s41591-019-0358-x",

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T1 - IL1R1 is required for celastrol’s leptin-sensitization and antiobesity effects

AU - Feng, Xudong

AU - Guan, Dongxian

AU - Auen, Thomas

AU - Choi, Jae Won

AU - Salazar Hernández, Mario Andrés

AU - Lee, Jaemin

AU - Chun, Hyonho

AU - Faruk, Farhana

AU - Kaplun, Esther

AU - Herbert, Zachary

AU - Copps, Kyle D.

AU - Ozcan, Umut

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

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JO - Nature Medicine

JF - Nature Medicine

IS - 4

ER -

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

Abstract

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