Treatment with celastrol protects against obesity through suppression of galanin-induced fat intake and activation of PGC-1α/GLUT4 axis-mediated glucose consumption

Abstract

Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus and hyperlipidemia. Despite years of progress in medicine, there are no highly effective pharmacological treatments for obesity. The natural compound celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, exerts various bioactivities including anti-diabetic and anti-obese effects. Although celastrol could decrease food intake and obesity, the detailed mechanism for celastrol is still unclear as yet. Herein, we intended to determine the effect of celastrol on obesity and the underlying mechanisms. In the present study, diet-induced obese mice were treated with 100 μg/kg/d celastrol for the last 21 days, and 3T3-L1 cells were treated with celastrol for 6 h. The present findings showed that celastrol suppresses fat intake, and leads to weight loss by inhibiting galanin and its receptor expression in the hypothalamus of mice fed a high-fat diet. More importantly, in addition to these direct anti-obesity activities, celastrol augmented the PGC-1α and GLUT4 expression in adipocytes and skeletal muscles to increase glucose uptake through AKT and P38 MAPK activation. Celastrol also inhibited gluconeogenic activity through a CREB/PGC-1α pathway. In conclusion, the weight-lowering effects of celastrol are driven by decreased galanin-induced food consumption. Thus, this study contributes to our understanding of the anti-obese role of celastrol, and provides a possibility of using celastrol to treat obesity in clinic.

Keywords: Celastrol; Galanin; Obesity.