Sulforaphane Reduces Obesity by Reversing Leptin Resistance
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PROVIDER: PRJNA752135 | ENA |
REPOSITORIES: ENA
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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:Histone Deacetylase 6 inhibition restores leptin sensitivity and reduces obesity
| PRJNA785995 | ENA
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:Leptin resistance during excess weigh gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of Leptin receptor b (LepR) signaling during obesity is still elusive. Here we report that histone deactylase 6 (HDAC6) interacts with LepR, reducing the latter’s activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of obese mice with blood brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to a potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in AgRP-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors result in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally-, but not peripherally-acting HDAC6 inhibitors as potent leptin-sensitizers and anti-obesity agents.
2024-01-09 | GSE252779 | GEO
Project description:Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, very few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we show that by combining FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic approaches (RNA-seq, ChIP-seq, ATAC-seq), we can provide a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. Further demonstrating the robustness of our leptin-response neuron regulome, we functionally characterize a novel enhancer near Socs3, a leptin response-associated transcription factor. Combined, our results provide a comprehensive map of active genomic regions in leptin-responsive neurons and present a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus.
2019-04-01 | GSE112125 | GEO
Project description:Aging contributes to many chronic conditions, including central obesity, insulin resistance and osteoporosis, which are also critical features of glucocorticoid excess. To investigate tissue-specific sites of glucocorticoid (GC) action during aging, we disrupted GC signalling in mouse osteoblasts via transgenic overexpression of the GC-inactivating enzyme, 11β-hydroxysteroid-dehydrogenase type 2 (11β-HSD2). Wild-type mice with intact osteoblastic GC signalling developed leptin resistance, obesity and insulin resistance with aging. In contrast, transgenic (HSD2OB-tg) mice remained lean and leptin-sensitive, and were protected against aging-related hyperinsulinaemia, blunted sympathetic responses and loss of thermogenic adipose tissue. These salutary effects were independent of the osteoblast-derived factors osteocalcin and lipocalin-2. Gene expression analysis of bones from HSD2OB-tg mice indicated an early induction of pro-osteogenic and anti-adipogenic factors, and activation of a local pro-inflammatory TLR4-ZBTB16-NR1H3 network in osteoblastic cells. These findings reveal a critical role for skeletal glucocorticoid signaling in central leptin action, and in impaired metabolic function with aging
2020-11-09 | GSE141448 | GEO
Project description: Not available
| S-EPMC3832894 | biostudies-literature
Project description:Obesity induces profound transcriptome changes in adipocytes; recent evidence suggests that lncRNAs play key roles in this process. Here, we performed a comprehensive transcriptome study by RNA-Seq in adipocytes isolated from interscapular brown, inguinal and epididymal white adipose tissues in diet-induced obese mice. Our analysis reveals a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in fed vs. fasted state, potentially serving as novel molecular markers reflecting adipose energy status. Among the most prominent ones is Lnc-leptin, an lncRNA transcribed from an enhancer region upstream of Leptin. Expression of Lnc-leptin is sensitive to insulin and closely correlates to Leptin expression across diverse pathophysiological conditions. Functionally, induction of Lnc-leptin is essential for adipogenesis, and its presence is required for a loop formation between exon2 of Lnc-leptin and promoter of Leptin in mature adipocytes and the maintenance of Leptin expression in vitro and in vivo. Our study establishes Lnc-leptin as a new regulator of Leptin.
2018-04-19 | GSE113315 | GEO
Project description:Skeletal glucocorticoid signaling determines aging-related leptin resistance and obesity
| PRJNA593512 | ENA
Project description:Pre- and postnatal calorie restriction is associated with postnatal growth restriction, reduced circulating leptin concentrations and perturbed energy balance. Hypothalamic regulation of energy balance demonstrates enhanced orexigenic (NPY, AgRP) and diminished anorexigenic (POMC, CART) neuropeptide expression (PN21) setting the stage for subsequent development of obesity. Leptin replenishment during the early postnatal period (PN2-PN8) led to reversing the hypothalamic orexigenic:anorexigenic neuropeptide ratio at PN21 by only reducing the orexigenic (NPY, AgRP) without affecting the anorexigenic (POMC, CART) neuropeptide expression. This hypothalamic effect was mediated via enhanced leptin receptor (ObRb) signaling that involved increased pSTAT3 but reduced PTP1B. This was further confirmed by an increase in body weight at PN21 in response to intracerebroventricular administration of antisense ObRb oligonucleotides (PN2-PN8). The change in the hypothalamic neuropeptide balance in response to leptin administration caused increased oxygen consumption, carbon dioxide production and physical activity which resulted in increased milk intake (PN14) with no change in body weight. This is in contrast to the reduction in milk intake with no effect on energy expenditure and physical activity observed in controls. We conclude that pre- and postnatal calorie restriction perturbs hypothalamic neuropeptide regulation of energy balance setting the stage for hyperphagia and reduced energy expenditure, hallmarks of obesity. Leptin in turn reverses this phenotype by increasing hypothalamic ObRb signaling (sensitivity) and affecting only the orexigenic arm of the neuropeptide balance.
2014-12-31 | GSE55384 | GEO