Celastrol, a triterpene derived from the thunder god vine (Tripterygium wilfordii), has shown promising efficacy in preclinical models for the treatment of metabolic disorders such as obesity and diabetes. The compound has anti-inflammatory properties and has been shown to improve insulin sensitivity and lipid metabolism. Its weight loss properties are attributed to an improvement in leptin sensitivity, most likely by targeting neural circuits in the hypothalamus that control food intake and appetite. Despite extensive research, the precise mechanism of action remains elusive. In this study, we aimed to investigate the metabolic effects of centrally administered celastrol in rodents. We show that subchronic intracerebroventricular (icv) 3 celastrol treatment in mice improved leptin sensitivity on a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp measurements in HFD-fed rats revealed improved glucose metabolism with acute icv 3 celastrol infusion. To elucidate the cellular targets mediating these effects, we used single nucleus RNA sequencing of hypothalamic leptin receptor-expressing cells. We show profound transcriptional effects of celastrol in distinct neuronal populations in a leptin-resistant state of diet-induced obese mice. Furthermore, we demonstrate restored leptin responsiveness after celastrol treatment, confirming leptin resensitization at the transcriptional level. Our findings reveal a weight loss-independent mechanism of action of celastrol in regulating glucose homeostasis and provide insights into potential molecular targets for the treatment of obesity and leptin resistance.