Home LiteratureArticle Details
PMID: 31407623 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis.

Adipocyte ·Vol. 8 ·No. 1 ·2019-00-00 ·Pages 318-329

Zhang Y, Zheng Y, Fu Y, Wang C

Abstract

For the better understanding of insulin resistance (IR), the molecular biomarkers in IR white adipocytes and its potential mechanism, we downloaded two mRNA expression profiles from Gene Expression Omnibus (GEO). The white adipocyte samples in two databases were collected from the human omental adipose tissue of IR obese (IRO) subjects and insulin-sensitive obese (ISO) subjects, respectively. We identified 86 differentially expressed genes (DEGs) between the IRO and ISO subjects using limma package in R software. Gene Set Enrichment Analysis (GSEA) provided evidence that the most gene sets enriched in kidney mesenchyme development in the ISO subjects, as compared with the IRO subjects. The Gene Ontology (GO) analysis indicated that the most significantly enriched in cellular response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the DEGs were most significantly enriched in cytokine-cytokine receptor interaction. Protein-Protein Interaction (PPI) network was performed with the STRING, and the top 10 hub genes were identified with the Cytohubba. CMap analysis found several small molecular compounds to reverse the altered DEGs, including dropropizine, aceclofenac, melatonin, and so on. Our outputs could empower the novel potential targets to treat omental white adipocyte insulin resistance, diabetes, and diabetes-related diseases.

Keywords
DEGs Insulin resistance bioinformatics hub gene omental adipocyte
MeSH Terms
Adipocytes, White/chemistry Computational Biology/methods Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulatory Networks Genetic Markers Insulin Resistance Obesity/genetics Oligonucleotide Array Sequence Analysis Omentum/chemistry
Chemicals
Genetic Markers
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Zhang Yemin
a Department of Pathology and Pathophysiology, Wuhan University School of Basic Medical Sciences , Wuhan , China. | b Hubei Provincial Key Laboratory of Developmentally Originated Disease , Wuhan , China.
Zheng Yuyang
a Department of Pathology and Pathophysiology, Wuhan University School of Basic Medical Sciences , Wuhan , China. | b Hubei Provincial Key Laboratory of Developmentally Originated Disease , Wuhan , China.
Fu Yalin
a Department of Pathology and Pathophysiology, Wuhan University School of Basic Medical Sciences , Wuhan , China. | b Hubei Provincial Key Laboratory of Developmentally Originated Disease , Wuhan , China.
Wang Changhua
a Department of Pathology and Pathophysiology, Wuhan University School of Basic Medical Sciences , Wuhan , China. | b Hubei Provincial Key Laboratory of Developmentally Originated Disease , Wuhan , China.
References (52)
52 references, click to expand
  1. The sva package for removing batch effects and other unwanted variation in high-throughput experiments.
    Bioinformatics. 2012 Mar 15;28(6):882-3 PMID: 22257669
  2. The Effect of Zinc Supplementation on Insulin Resistance in Obese Subjects: a Systematic Review.
    Biol Trace Elem Res. 2017 Apr;176(2):239-243 PMID: 27587022
  3. Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ.
    Theranostics. 2018 Mar 8;8(8):2171-2188 PMID: 29721071
  4. COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver.
    Obesity (Silver Spring). 2009 Jun;17(6):1150-7 PMID: 19247274
  5. Mechanisms of insulin resistance in obesity.
    Front Med. 2013 Mar;7(1):14-24 PMID: 23471659
  6. cytoHubba: identifying hub objects and sub-networks from complex interactome.
    BMC Syst Biol. 2014;8 Suppl 4:S11 PMID: 25521941
  7. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications.
    Hepatology. 2010 Feb;51(2):679-89 PMID: 20041406
  8. Obesity-associated insulin resistance is correlated to adipose tissue vascular endothelial growth factors and metalloproteinase levels.
    BMC Physiol. 2012 Apr 02;12:4 PMID: 22471305
  9. The relationship of omental and subcutaneous adipocyte size to metabolic disease in severe obesity.
    PLoS One. 2010 Apr 01;5(4):e9997 PMID: 20376319
  10. Inhibitory effect of IL-8 on insulin action in human adipocytes via MAP kinase pathway.
    J Inflamm (Lond). 2009 Aug 27;6:25 PMID: 19709445
  11. miR-1934, downregulated in obesity, protects against low-grade inflammation in adipocytes.
    Mol Cell Endocrinol. 2016 Jun 15;428:109-17 PMID: 27013351
  12. Obesity and insulin resistance.
    J Clin Invest. 2000 Aug;106(4):473-81 PMID: 10953022
  13. Adipose inflammation, insulin resistance, and cardiovascular disease.
    JPEN J Parenter Enteral Nutr. 2008 Nov-Dec;32(6):638-44 PMID: 18974244
  14. Interferon-gamma released from omental adipose tissue of insulin-resistant humans alters adipocyte phenotype and impairs response to insulin and adiponectin release.
    Int J Obes (Lond). 2017 Dec;41(12):1782-1789 PMID: 28769120
  15. Extracellular vesicles in obesity and diabetes mellitus.
    Mol Aspects Med. 2018 Apr;60:81-91 PMID: 29175307
  16. limma powers differential expression analyses for RNA-sequencing and microarray studies.
    Nucleic Acids Res. 2015 Apr 20;43(7):e47 PMID: 25605792
  17. Exosomes As Potential Biomarkers and Targeted Therapy in Colorectal Cancer: A Mini-Review.
    Front Pharmacol. 2017 Aug 28;8:583 PMID: 28894420
  18. HeatmapGenerator: high performance RNAseq and microarray visualization software suite to examine differential gene expression levels using an R and C++ hybrid computational pipeline.
    Source Code Biol Med. 2014 Dec 24;9(1):30 PMID: 25550709
  19. Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation.
    Sci Rep. 2016 Jun 02;6:27236 PMID: 27250532
  20. STRING v9.1: protein-protein interaction networks, with increased coverage and integration.
    Nucleic Acids Res. 2013 Jan;41(Database issue):D808-15 PMID: 23203871
  21. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders.
    Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3463-8 PMID: 25733901
  22. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles.
    Cell. 2017 Nov 30;171(6):1437-1452.e17 PMID: 29195078
  23. Adipogenesis and metabolic health.
    Nat Rev Mol Cell Biol. 2019 Apr;20(4):242-258 PMID: 30610207
  24. Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle.
    J Pineal Res. 2014 Sep;57(2):155-67 PMID: 24981026
  25. The citrus flavonoids hesperetin and naringenin block the lipolytic actions of TNF-alpha in mouse adipocytes.
    Biochem Biophys Res Commun. 2010 Apr 9;394(3):728-32 PMID: 20230793
  26. The Gene Expression Omnibus Database.
    Methods Mol Biol. 2016;1418:93-110 PMID: 27008011
  27. Fas and FasL expression in human adipose tissue is related to obesity, insulin resistance, and type 2 diabetes.
    J Clin Endocrinol Metab. 2014 Jan;99(1):E36-44 PMID: 24178789
  28. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.
    Nat Rev Endocrinol. 2016 Mar;12(3):144-53 PMID: 26678809
  29. Adipose tissue, adipokines, and inflammation.
    J Allergy Clin Immunol. 2005 May;115(5):911-9; quiz 920 PMID: 15867843
  30. High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun.
    Diabetes. 2016 Mar;65(3):619-32 PMID: 26825459
  31. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals.
    Diab Vasc Dis Res. 2005 Oct;2(3):105-12 PMID: 16334591
  32. Matrix metalloproteinase-9 is increased in obese subjects and decreases in response to pioglitazone.
    J Clin Endocrinol Metab. 2010 Jun;95(6):2993-3001 PMID: 20392866
  33. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  34. Macrophage Lamin A/C Regulates Inflammation and the Development of Obesity-Induced Insulin Resistance.
    Front Immunol. 2018 Apr 20;9:696 PMID: 29731750
  35. Visceral adiposity, insulin resistance and cancer risk.
    Diabetol Metab Syndr. 2011 Jun 22;3:12 PMID: 21696633
  36. Adipocyte exosomes induce transforming growth factor beta pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease.
    J Surg Res. 2014 Dec;192(2):268-75 PMID: 25086727
  37. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.
    Nucleic Acids Res. 2009 Jan;37(1):1-13 PMID: 19033363
  38. Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation.
    J Cancer. 2016 Nov 26;7(15):2346-2359 PMID: 27994674
  39. Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats.
    Cardiovasc J Afr. 2017 Nov/Dec 23;28(6):362-369 PMID: 28556852
  40. The role of interleukin-6 in insulin resistance, body fat distribution and energy balance.
    Obes Rev. 2008 Jan;9(1):20-9 PMID: 17956545
  41. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
    J Clin Invest. 2006 Jun;116(6):1494-505 PMID: 16691291
  42. Insulin resistance adipocyte-derived exosomes aggravate atherosclerosis by increasing vasa vasorum angiogenesis in diabetic ApoE-/- mice.
    Int J Cardiol. 2018 Aug 15;265:181-187 PMID: 29685689
  43. MultiContrast Delayed Enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study.
    J Cardiovasc Magn Reson. 2012 Nov 30;14:83 PMID: 23199362
  44. Hyperglycemia, tumorigenesis, and chronic inflammation.
    Crit Rev Oncol Hematol. 2016 Dec;108:146-153 PMID: 27931833
  45. The links between insulin resistance, diabetes, and cancer.
    Curr Diab Rep. 2013 Apr;13(2):213-22 PMID: 23271574
  46. The role of melatonin in diabetes: therapeutic implications.
    Arch Endocrinol Metab. 2015 Oct;59(5):391-9 PMID: 26331226
  47. Exosomes: novel biomarkers for clinical diagnosis.
    ScientificWorldJournal. 2015;2015:657086 PMID: 25695100
  48. Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells.
    Oncotarget. 2017 Jun 27;8(47):81880-81891 PMID: 29137230
  49. Withaferin A Protects Against High-Fat Diet-Induced Obesity Via Attenuation of Oxidative Stress, Inflammation, and Insulin Resistance.
    Appl Biochem Biotechnol. 2019 May;188(1):241-259 PMID: 30417321
  50. Bone morphogenetic protein-7 (BMP-7) augments insulin sensitivity in mice with type II diabetes mellitus by potentiating PI3K/AKT pathway.
    Biofactors. 2017 Mar;43(2):195-209 PMID: 28186649
  51. A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility.
    Genome Res. 2008 May;18(5):706-16 PMID: 18347327
  52. Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity.
    Surg Obes Relat Dis. 2011 Jan-Feb;7(1):60-7 PMID: 20678967
Article Info
Journal
Adipocyte
Abbr.
Adipocyte
ISSN
2162-397X
Published
2019-00-00
Pages
318-329
Language
English
Region
United States
NLM ID
101567863
PMCID
PMC6768254
Subset
IM
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]