Direct Action of Celastrol on Hypothalamic ARC Neurons to Increase Leptin Sensitivity

Abstract

Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Individuals with obesity generally exhibit hyperleptinemia and leptin resistance. Leptin sensitizers, rather than leptin, are expected to act as anti-obesity drugs. Recently, celastrol was identified as a leptin sensitizer. Celastrol alleviated endoplasmic reticulum (ER) stress and restored leptin sensitivity in the hypothalamus. However, the molecular mechanisms and sites of action of celastrol remain poorly understood. In this study, after confirming the effect of celastrol on body weight, food intake, and leptin sensitivity in lean and diet-induced obese (DIO) mice, we investigated the direct effect of celastrol on arcuate nucleus (ARC) neurons isolated from the hypothalamus by monitoring the intracellular calcium concentrations ([Ca2+]i). Celastrol treatment significantly decreased body weight gain and food intake, and significantly augmented leptin actions on food intake and hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation in both lean and DIO mice. In accordance with these results, celastrol treatment enhanced [Ca2+]i response to leptin in the ARC neurons of both lean and DIO mice. To our knowledge, this is the first report to demonstrate the direct effect of celastrol on ARC neurons. This knowledge might shed light on the molecular mechanisms underlying celastrol-induced leptin sensitization and resistance.departmental bulletin pape