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Treatment of obesity with celastrol.

ABSTRACT: Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity.

SUBMITTER: Liu J

PROVIDER: S-EPMC4768733 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Treatment of obesity with celastrol.

Liu Junli J Lee Jaemin J Salazar Hernandez Mario Andres MA Mazitschek Ralph R Ozcan Umut U

Cell 20150501 5

Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obes ...[more]

PMID: 26000480

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Effects of Microbiota on the Treatment of Obesity with the Natural Product Celastrol in Rats.

Project description:BackgroundObesity has become one of the most serious issues threatening the health of humankind, and we conducted this study to examine whether and how celastrol protects against obesity.MethodsWe fed male Sprague-Dawley rats a high-fat diet and administered celastrol to obese rats for 3 weeks. By recording body weight (BW) and other measures, we identified the effective dose of celastrol for obesity treatment. Feces were collected to perform 16S rRNA sequencing, and hypothalami were extracted for transcriptome sequencing. We then treated leptin knockout rats with celastrol and explored the changes in energy metabolism. Male Institute of Cancer Research (ICR) mice were used to test the acute toxicity of celastrol.ResultsWe observed that celastrol reduced BW and promoted energy expenditure at a dose of 500 µg/kg BW but that food intake was not changed after administration. The diversity of the gut microbiota was improved, with an increased ratio of Bacteroidetes to Firmicutes, and the gut microbiota played an important role in the anti-obesity effects of celastrol. Hypothalamic transcriptome analysis showed a significant enrichment of the leptin signaling pathway, and we found that celastrol significantly enhanced energy expenditure, which was mediated by the leptin signaling pathway. Acute lethal toxicity of celastrol was not observed at doses ranging from 0 to 62.5 mg/kg BW.ConclusionOur study revealed that celastrol decreased the BW of obese rats by enhancing energy expenditure but not by suppressing food intake and that this effect was mediated by the improvement of the gut microbiota and the activation of the hypothalamic leptin signaling pathway.

| S-EPMC7643605 | biostudies-literature

The leptin sensitizer celastrol reduces age-associated obesity and modulates behavioral rhythms.

Project description:The prevalence of obesity increases with age in humans and in rodents. Age-related obesity is characterized by leptin resistance and associated with heightened risk of metabolic disorders. However, the effect of leptin resistance per se has been difficult to disentangle from other effects of aging. Here we demonstrate that celastrol, a natural phytochemical that was previously shown to act as a leptin sensitizer, induces weight loss in aged animals, but not in young controls. Celastrol reduces food intake and lowers fasting glucose without affecting energy expenditure. Unexpectedly, administration of celastrol just before the dark period disrupted circadian rhythms of sleep and activity. This regimen was also associated with loss of lean mass an outcome that would not be desirable in elderly patients. Adjusting the timing of celastrol administration by 12 hr, to the beginning of the light period, avoided interference with circadian rhythms while retaining the reductions in body weight and adiposity. Thus, targeting leptin signaling is an effective strategy to ameliorate age-associated weight gain, and can profoundly impact circadian rhythms.

| S-EPMC6516176 | biostudies-literature

Celastrol treatment on mouse embryonic fibroblasts (MEFs)

Project description:Celastrol has been shown to sensitize leptin receptor signaling and reduce ER stress. Current microarray data provide the gene expression profile in mouse embryonic fibroblasts (MEFs) after Celastrol treatment compared with control.

2016-07-08 | GSE84154 | GEO

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases.

Project description:The identification of new bioactive compounds derived from medicinal plants with significant therapeutic properties has attracted considerable interest in recent years. Such is the case of the Tripterygium wilfordii (TW), an herb used in Chinese medicine. Clinical trials performed so far using its root extracts have shown impressive therapeutic properties but also revealed substantial gastrointestinal side effects. The most promising bioactive compound obtained from TW is celastrol. During the last decade, an increasing number of studies were published highlighting the medicinal usefulness of celastrol in diverse clinical areas. Here we systematically review the mechanism of action and the therapeutic properties of celastrol in inflammatory diseases, namely, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, osteoarthritis and allergy, as well as in cancer, neurodegenerative disorders and other diseases, such as diabetes, obesity, atherosclerosis, and hearing loss. We will also focus in the toxicological profile and limitations of celastrol formulation, namely, solubility, bioavailability, and dosage issues that still limit its further clinical application and usefulness.

| S-EPMC5471334 | biostudies-literature

Celastrol prevents high-fat diet-induced obesity by promoting white adipose tissue browning.

Project description: Not available

| S-EPMC8673360 | biostudies-literature

Creation of an Anti-Inflammatory, Leptin-Dependent Anti-Obesity Celastrol Mimic with Better Druggability.

Project description:Obesity is characterized by an excessive body mass, but is also closely associated with metabolic syndrome. And, so far, only limited pharmacological treatments are available for obesity management. Celastrol, a pentacyclic triterpenoid from a traditional Chinese medicine (Tripterygium wilfordii Hook.f.), has shown remarkable potency against obesity, inflammation and cancer, but its high toxicity, low natural abundance and tedious chemical synthesis hindered its translation into clinics. In the present work, a triterpenoid library was screened for compounds with both high natural abundance and structural similarity to celastrol; from this library, glycyrrhetinic acid (GA), a compound present in extremely high yields in Glycyrrhiza uralensis Fisch. ex DC., was selected as a possible scaffold for a celastrol mimic active against obesity. A simple chemical modification of GA resulted in GA-02, a derivative that suppressed 68% of food intake in diet-induced obesity mice and led to 26.4% weight loss in 2 weeks. GA-02 plays a role in obesity treatment by re-activating leptin signaling and reducing systemic and, more importantly, hypothalamic inflammation. GA-02 was readily bioavailable with unnoticeable in vitro and in vivo toxicities. The strategy of scaffold search and modification on the basis of bio-content and structural similarity has proved to be a green, economic, efficient and practical way of widening the medicinal applications of "imperfect" bioactive natural compounds.

| S-EPMC8435713 | biostudies-literature

Celastrol alleviates comorbid obesity and depression by directly binding amygdala HnRNPA1 in a mouse model.

Project description: Not available

| S-EPMC8181197 | biostudies-literature

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

Project description:Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the Tripterygium wilfordii and known to reduce endoplasmic reticulum (ER) stress, has recently emerged as a promising candidate to treat obesity by improving leptin sensitivity. However, the underlying neural mechanisms by which celastrol reduces obesity remain unclear. Using three different mouse models of obesity-diet-induced obesity (DIO), leptin receptor (LepR)-null, and melanocortin 4 receptor (MC4R)-null mice-in this study, we show that systemic celastrol administration substantially reduces food intake and body weight in MC4R-null comparable to DIO, proving the MC4R-independent antiobesity effect of celastrol. Body weight reduction was due to decreases in both fat and lean mass, and modest but significant body weight reduction was also observed in nonobese wild-type and LepR-null mice. Unexpectedly, celastrol upregulated proinflammatory cytokines without affecting genes involved in ER stress. Importantly, celastrol steadily increased sympathetic nerve activity to the brown fat and kidney with concordant increases of resting metabolic rate and arterial pressure. Our results suggest a previously unappreciated mechanism of action of celastrol in the regulation of energy homeostasis and highlight the need for careful consideration of its development as a safe antiobesity medication.

| S-EPMC6610022 | biostudies-literature

Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity.

Project description:Celastrol, a compound extracted from traditional Chinese medicine, has been reported as a potent anti-obesity agent with controversial mechanisms. Here both C57BL/6J and leptin-deficient (ob/ob) mice fed a high-fat diet (HFD) displayed body weight loss after celastrol therapy, opposing the previous viewpoint that celastrol improves obesity by sensitizing leptin signaling. More importantly, celastrol downregulated lipid transporters in the intestine, increased lipid excretion in feces, and reduced body weight gain in HFD mice. Meanwhile, analysis of gut microbiota revealed that celastrol altered the gut microbiota composition in HFD-fed mice, and modulating gut microbiota by antibiotics or fecal microbiota transplantation blocked the celastrol effect on intestinal lipid transport and body weight gain, suggesting a critical role of the gut microbiota composition in mediating the anti-obesity role of celastrol under HFD. Together, the findings revealed that celastrol reduces intestinal lipid absorption to antagonize obesity by resetting the gut microbiota profile under HFD feeding.

| S-EPMC7868996 | biostudies-literature

Celastrol-loaded PEG-b-PPS nanocarriers as an anti-inflammatory treatment for atherosclerosis.

Project description:In this work, the hydrophobic small molecule NF-?B inhibitor celastrol was loaded into poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) micelles. PEG-b-PPS micelles demonstrated high loading efficiency, low polydispersity, and no morphological changes upon loading with celastrol. Encapsulation of celastrol within these nanocarriers significantly reduced cytotoxicity compared to free celastrol, while simultaneously expanding the lower concentration range for effective inhibition of NF-?B signaling by nearly 50?000-fold. Furthermore, celastrol-loaded micelles successfully reduced TNF-? secretion after LPS stimulation of RAW 264.7 cells and reduced the number of neutrophils and inflammatory monocytes within atherosclerotic plaques of ldlr-/- mice. This reduction in inflammatory cells was matched by a reduction in plaque area, suggesting that celastrol-loaded nanocarriers may serve as an anti-inflammatory treatment for atherosclerosis.

| S-EPMC6368678 | biostudies-literature

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