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| Status |
Public on Jan 22, 2022 |
| Title |
Sulforaphane Reduces Obesity by Reversing Leptin Resistance |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Transcriptome profiles in 6 metabolically active tissues of sulforaphane-treated diet-induced obese 28-week-old wild type (WT) mice.
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| Contributor(s) |
Çakır I, Lining Pan P, Hadley CK, El-Gamal A, Fadel A, Elsayegh D, Fadel A, Rizk NM, Ghamari-Langroudi M |
| Citation(s) |
35323110 |
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| Submission date |
Aug 04, 2021 |
| Last update date |
Mar 31, 2022 |
| Contact name |
Masoud Ghamari-Langroudi |
| E-mail(s) |
masoud.ghamari-langroudi@vanderbilt.edu
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| Phone |
6156383711
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| Organization name |
Vanderbilt University
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| Street address |
8435 MRB #IV, 2215 Garland ave
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| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (60)
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| Relations |
| BioProject |
PRJNA752135 |
| SRA |
SRP331158 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE181477_Differentially_Expressed_Genes_SFN_effects_all_tissues.xlsx |
6.6 Mb |
(ftp)(http) |
XLSX |
| GSE181477_FPKM_all_samples.xlsx |
25.4 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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