The leptin sensitizer celastrol reduces age-associated obesity and modulates behavioral rhythms.
Ontology highlight
ABSTRACT:
SUBMITTER: Chellappa K
PROVIDER: S-EPMC6516176 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
The leptin sensitizer celastrol reduces age-associated obesity and modulates behavioral rhythms.
Chellappa Karthikeyani K Perron Isaac J IJ Naidoo Nirinjini N Baur Joseph A JA
Aging cell 20190301 3
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 f ...[more]
Similar Datasets
Project description:Introduction: The ascending prevalence of obesity in recent decades is commonly associated with soaring rates of morbidity and mortality resulting in increased health care costs and decreased quality of life. A systemic state of stress characterized by low grade inflammation and pathologic formation of reactive oxygen species (ROS) usually manifest in obesity. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) is the master regulator of the redox homeostasis and plays a critical role in the resolution of inflammation. Our results indicate that the natural isothiocyanate and potent NRF2 activator sulforaphane reverses the diet-induced obesity in rodents and implicate involvement of leptin receptor singling in this effect. Purpose: Here, we investigate molecular pathways underlying the effects of sulforaphane in reversing diet-induced obesity and interrogate potential pathways that link NRF2 with leptin receptor signaling by conducting whole transcriptome analysis in 6 metabolically active tissues from the diet-induced obese mice that were treated with SFN. Methods: Male 12-week-old C57/BJ wild type mice were fed with high fat diet for 16-20 weeks. Around 28 weeks of age, mice were treated with daily ip injections of either SFN (5 mg/kg) or vehicle for one week. We probed the whole transcriptome in several metabolic tissues including the hypothalamus, liver, brown adipose tissue (BAT), epididymal white adipose tissue (eWAT), inguinal white adipose tissue (iWAT), and skeletal muscle following peripheral SFN administration. Total RNA samples from each tissue were prepared with Trizol. Whole transcriptome were conducted by using Novogene sequencing platform NovaSeq 6000 PE150. The following bioinformatics analysis have been conducted. 1. Data Quality Control: filtering reads containing adapter or with low quality. 2. Statistics Analysis of Data Production and Quality. 3. Mapping Reads to Reference Genome. 4. Gene Expression Quantification. 5. Correlation analysis (For biological replicates only). 6. Differential Expression Analysis (two or more groups of samples). 7. GO Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 8. KEGG Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 9. GSEA Enrichment Analysis of Expressed Genes (two or more groups of samples). 10. Protein Protein Interaction Analysis. 11. Reactome Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse samples). 12. Oncogene Functional Annotation analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse sample). Results: RNAseq results indicated a significant upregulation of the NRF2 target gene HMOX1 only in the skeletal muscle. We also conducted an enrichment analysis to identify potential transcription factors for the significantly upregulated genes. NRF2 was identified as the most significant transcription factor only for the skeletal muscle gene set, providing further support for the skeletal muscle being a primary target tissue of SFN action. We thus conducted a KEGG and GO pathway analysis, and identified ribosome biogenesis, proteasome pathway, and the RNA transport as the significantly upregulated pathways in the SFN-treated muscle samples. In addition to HMOX1, the RNA seq results indicate upregulation of other genes involved in oxidative stress response capacity in SFN treated mice in the skeletal muscle. GCLM (glutamate-cysteine ligase), the first rate-limiting enzyme of glutathione synthesis, SRXN1 (Sulfiredoxin), an oxidoreductase that reduces cysteine-sulfinate, and GSR (glutathione-disulfide reductase), a central antioxidant enzyme, which reduces oxidized glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), and TXNRD1 (thioredoxin reductase 1) which reduces thioredoxins are all upregulated in the skeletal muscle of the SFN-treated DIO animals. Conclusions: Here, we show that the natural isothiocyanate and potent NRF2 activator sulforaphane reverses diet-induced obesity through an NRF2-dependent mechanism that requires a functional leptin receptor signaling and hyperleptinemia. Transcriptional profiling of six major metabolically relevant tissues highlights that sulforaphane suppresses fatty acid synthesis while promoting ribosome biogenesis, reducing ROS accumulation and resolving inflammation, therefore representing a unique transcriptional program that leads to protection from obesity. Our findings argue for clinical evaluation of sulforaphane for weight loss and obesity-associated metabolic disorders.
2022-01-22 | GSE181477 | GEO
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
Project description:To further identify the mostly influenced signal pathways under Kdm6 inhibitor treatment, the microarray analysis was performed to screen the gene expression profile in the hypothalamus of DIO mice. The DIO mice were administrated with vehicle or 30 mg/kg GSK-J4 i.p. for 4 days. Totally, 205 genes were up regulated over 2 fold and 845 genes were down regulated over 2 fold.
2021-05-01 | GSE115113 | GEO
Project description:Introduction: Obesity and overweight affect more than one third of the world population, and are significant risk factors for type II diabetes, cardiovascular disease and cancer. Common obesity is usually accompanied by hyperleptinemia and leptin resistance. Purpose: Here, we investigate the molecular pathways underlying the effects of HDAC6 inhibition in reversing diet-induced obesity and interrogate potential pathways that link HDAC6 with leptin receptor signaling by conducting whole transcriptome analysis in white adipose tissues of the diet-induced obese mice that were treated with tubastatin A (an HDAC6-specific inhibitor) and in fat-specific HDAC6 knockout mice. Methods: Male 4-5 week-old C57B/6J wild type mice were fed with high fat diet for 16-20 weeks to generate diet-induced obese (DIO) mice. Around 28 weeks of age, mice were treated with daily ip injections of either tubastatin A-HCl (TubA, 25 mg/kg) or vehicle for four days. We probed the whole transcriptome in epididymal white adipose tissue (eWAT), and inguinal white adipose tissue (iWAT) following vehicle or TubA administration (eWAT.Veh, eWAT.TubA, iWAT.Veh, iWAT.TubA groups). In a separate cohort, DIO HDAC6 global knockout mice were treated with vehicle (Veh group) or TubA (TubA group). eWAT was excised for RNA extraction. In the third cohort, adipose tissue specific HDAC6 knockout mice were generated crossing adiponectin-Cre mice with HDAC6-floxed mice. These fat specific HDAC6 KO mice (AdKO) and their adiponectin-Cre controls (AdCre) were treated with vehicle for five weeks. eWAT was excised for RNA extraction.Total RNA samples from each tissue were extracted using Trizol. RNA Sequencing for the wild-type iWAT and eWAT samples from vehicle or TubA-treated mice was performed by the University of Michigan Sequencing Core, using the Illumina Hi-Seq 4000 platform. RNA sequencing for the other samples were conducted by Novogene, NovaSeq 6000 PE150, HiSeq SE50 platform. The following bioinformatics analysis have been conducted by Novogene: 1. Data Quality Control: filtering reads containing adapter or with low quality. 2. Statistics Analysis of Data Production and Quality. 3. Mapping Reads to Reference Genome. 4. Gene Expression Quantification. 5. Correlation analysis (For biological replicates only). 6. Differential Expression Analysis (two or more groups of samples). 7. GO Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 8. KEGG Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples). 9. GSEA Enrichment Analysis of Expressed Genes (two or more groups of samples). 10. Protein Protein Interaction Analysis. 11. Reactome Pathway Enrichment Analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse samples). 12. Oncogene Functional Annotation analysis of Differentially Expressed Genes (DEGs) (two or more groups of samples and only for mouse sample). Results: Inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent anti-obesity agents, and leptin sensitizers. HDAC6 inhibitor TubA suppresses food intake and reduce obesity, in an HDAC6-dependent manner, resulting in up to fifty percent decrease in fat mass in DIO mice accompanied by significantly reduced hepatic steatosis and improved systemic glucose homeostasis. Conclusions: Mechanistically, peripheral -but not central- inhibition of HDAC6 confers central leptin sensitivity, and the anti-obesity effect of TubA is significantly attenuated in animals defective in the central leptin-melanocortin circuitry, including the db/db and MCR4 KO mice.
2021-12-05 | GSE190156 | GEO
Project description:Sulforaphane Reduces Obesity by Reversing Leptin Resistance
| PRJNA752135 | ENA
Project description:The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin's actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R knockout mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent and reveals HDAC6 as a potential target for the treatment of obesity.
| S-EPMC8892841 | biostudies-literature
Project description: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.
| S-EPMC4768733 | biostudies-literature
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
Project description:Leptin triggers signaling events with significant transcriptional responses that are essential to metabolic processes affecting obesity and glucose disposal. We asked whether hexamethylene bis-acetamide inducible-1 (Hexim1), an inhibitor of RNA II polymerase-dependent transcription elongation, regulates leptin-Janus kinase 2 signaling axis in the hypothalamus. We subjected C57BL6 Hexim1 heterozygous (HT) mice to high-fat diet and when compared with wild type, HT mice were resistant to high-fat diet-induced weight gain and remain insulin sensitive. HT mice exhibited increased leptin-pY(705)Stat3 signaling in the hypothalamus, with normal adipocyte size, increased type I oxidative muscle fiber density, and enhanced glucose transporter 4 expression. We also observed that normal Hexim1 protein level is required to facilitate the expression of CCAAT/enhancer-binding proteins (C/EBPs) required for adipogenesis and inducible suppressor of cytokine signaling 3 (SOCS) expression. Further support on the role of Hexim1 regulating C/EBPs during adipocyte differentiation was shown when HT 3T3L1 fibroblasts failed to undergo adipogenesis. Hexim1 selectively modulates leptin-mediated signal transduction pathways in the hypothalamus, the expression of C/EBPs and peroxisome proliferator-activated receptor-? (PPAR ?) in skeletal muscle and adipose tissue during the adaptation to metabolic stress. We postulate that Hexim1 might be a novel factor involved in maintaining whole-body energy balance.
| S-EPMC4771697 | biostudies-other
Project description:In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.
| S-EPMC4517239 | biostudies-other