Celastrol, a pentacyclic triterpene is the most potent anti-obesity agent that has been reported to date 1. The mechanism of celastrol's leptin sensitizing and anti-obesity effects has not yet been elucidated. In this study, we identified interleukin 1 receptor 1 (IL1R1) as a mediator of celastrol 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 celastrol's leptin sensitization, anti-obesity, anti-diabetic and anti-NASH effects. Thus, we conclude that IL1R1 is a gate-keeper for celastrol's metabolic actions. Increased ER stress in the hypothalamus plays a central role in the development of leptin resistance, and thus obesity 2-5. Given these findings, we undertook in silico screens utilizing systems biology approaches to identify new chemical chaperones that would serve as stronger leptin sensitizers. These efforts yielded celastrol, a pentacyclic triterpene as a potentially efficacious chemical chaperone and leptin sensitizer 1. Celastrol reduces the body weight of diet-induced obese (DIO) mice by 45-50% and further ameliorates insulin resistance/type-2 diabetes, nonalcoholic steatohepatitis (NASH), hypercholesterolemia, and liver damage in DIO mice 1. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

No abstract

ObjectivePeroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism.MethodsWe investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models.ResultsWe show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction.ConclusionsOur findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s.