307-LB: IL1R1 Mediates Celastrol’s Leptin-Sensitization and Antiobesity Effects

Abstract

Celastrol, isolated from the root extracts of thunder god vine, is the most potent anti-obesity agent that has been reported to date. Celastrol increases leptin sensitivity in the hyperleptinemic diet-induced obese (DIO) mice and leads to 45-50% weight loss in this model, with either no or only marginal effects in db/db, ob/ob or lean mice. In this work, we first showed that lipocalin 2 (LCN2) is the most upregulated gene in the hypothalamus of DIO mice after celastrol treatment. Celastrol treatment leads to a significant upregulation of LCN2 both in bone marrow, plasma, and the hypothalamus. However, LCN2 does not play a significant role in suppressing appetite and reducing body weight or mediating celastrol’s antiobesity effects. Secondly, by using systems biology approaches for analysis of temporal regulations of the hypothalamic transcriptome of DIO, lean and db/db mice that were treated with celastrol, we have identified interleukin 1 receptor 1 (IL1R1) as a mediator of celastrol action and documented that IL1R1-deficient mice is completely resistant to celastrol’s leptin sensitization, anti-obesity, antidiabetic and anti-NASH effects. Thus, IL1R1 is a gate-keeper for celastrol’s metabolic actions. Disclosure X. Feng: None. Funding Fidelity Biosciences Research Initiative