Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1

Abstract

Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep mice respond with a decrease in food intake and body weight, adult Lep and Lep mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.

Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions

“…The mechanisms by which celastrol reduces obesity have been controversial. An initial study (10) and recent report (12) attributed the weight-reducing effects of celastrol to its anorectic action, whereas another report indicated energy expenditure but not food intake (11). Although our observations seem to agree with both models, there are also differences between our findings and previous reports.…”

“…Notably, a recent study of active screening for small compounds ameliorating ER stress led to a discovery of celastrol, a small molecule found in the roots of the Tripterygium wilfordii plant, as a promising candidate to restore leptin sensitivity and dramatically reduce body weight in a mouse model of metabolic syndrome, diet-induced obesity (DIO) (10). The body weight-reducing effect of celastrol was remarkable and repeated independently in other studies soon after its discovery (11,12), although the proposed underlying mechanisms appear discordant. Similarly interesting is that the induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) exclusively in proopiomelanocortin (Pomc) neurons (a unique source producing the endogenous melanocortin 4 receptor [MC4R] agonist in the brain) alone is sufficient to protect the mice from DIO and improve leptin sensitivity (13), whereas Pomc-specific ablation of mitofusin-2 (Mfn2) results in ER stress-induced leptin resistance and obesity (14), underscoring the importance of the central melanocortin pathway in the development of obesity associated with ER stress.…”

The Gut Microbiota and Its Metabolites, Novel Targets for Treating and Preventing Non‐Alcoholic Fatty Liver Disease

“…[106] This reversal effect was also demonstrated in FMT experiments, further highlighting the role of gut microbiota in obesity-related metabolic diseases. In addition, a plant-derived Chinese medicine, Celastrol, showed a marked anti-obesity effect in HFD-induced obese mice, [107] and Feng et al identified IL-1 receptor 1 as a key mediator alleviating liver disruption, such as hepatic steatosis and liver IR. [108] However, further studies are required to specify the main effective compounds and key targets responsible for preventing and treating liver disorders.…”

Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

“…We recently reported that C57BL/6J mice on high-fat diet (HFD) responded to DSF treatment with a decrease in body weight and an increase in energy expenditure without a significant change in food intake 8 . In contrast to the leptin sensitizer celastrol 9 and the incretin-dexamethasone conjugate 10 , DSF did not induce hypophagia. The intervention with DSF improved glucose tolerance and insulin sensitivity, while preventing fibrosis and steatosis of the liver and hypertrophy of pancreatic islet cells.…”