Endocrine Abstracts

Celastrol, a triterpene compound derived from the thunder god vine (Tripterygium wilfordii), has shown promising efficacy in preclinical models for the management of metabolic disorders such as obesity and diabetes. The compound exhibits anti-inflammatory properties and has been shown to enhance insulin sensitivity and modulate lipid metabolism. The observed weight loss effects are thought to be primarily mediated by its ability to augment leptin sensitivity. Despite extensive research, its exact mode of action remains poorly understood. We and others suggested that the therapeutic effects of celastrol may, to a large extent, be mediated by the hypothalamus and its neural circuits that control food intake and appetite. However, no studies to date had explored the direct metabolic effects of celastrol after central application. In this study, we aimed to specifically examine whether centrally administered celastrol can regulate energy and glucose metabolism in rodents. Using mice, we show that the subchronic treatment with intracerebroventricular (icv) 3 celastrol improves sensitivity to leptin in animals that were fed a high-fat diet. By hyperinsulinemic-euglycemic clamp measurements we further demonstrate that rats fed a high-fat diet exhibit improved glucose metabolism when acutely infused with icv 3 celastrol. In order to determine cellular targets mediating these effects, we employed single nucleus RNA sequencing of hypothalamic leptin receptor-expressing cells. We reveal dramatic transcriptional effects of celastrol in a leptin resistant state of diet-induced obese mice as well as the transcriptional signature of leptin together with a celastrol pre-treatment. Our results suggest a previously unappreciated weight loss-independent mechanism of action of celastrol in the regulation of glucose homeostasis and new insights for potential molecular targets in the treatment of obesity and leptin resistance.