Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects
1 FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Tukholmankatu 8, Helsinki 00290, Finland
2 Public Health Genomics Unit, National Institute for Health and Welfare, Haartmaninkatu 8, Helsinki 00290, Finland
3 Department of Medicine, Division of Diabetes, Helsinki University Central Hospital, Haartmaninkatu 8, Helsinki 00290, Finland
4 Minerva Foundation Institute for Medical Research, Tukholmankatu 8, Helsinki 00290, Finland
BMC Medical Genomics 2012, 5:9 doi:10.1186/1755-8794-5-9Published: 3 April 2012
To get insight into molecular mechanisms underlying insulin resistance, we compared acute in vivo effects of insulin on adipose tissue transcriptional profiles between obese insulin-resistant and lean insulin-sensitive women.
Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 hours of intravenously maintained euglycemic hyperinsulinemia from 9 insulin-resistant and 11 insulin-sensitive females. Gene expression was measured using Affymetrix HG U133 Plus 2 microarrays and qRT-PCR. Microarray data and pathway analyses were performed with Chipster v1.4.2 and by using in-house developed nonparametric pathway analysis software.
The most prominent difference in gene expression of the insulin-resistant group during hyperinsulinemia was reduced transcription of nuclear genes involved in mitochondrial respiration (mitochondrial respiratory chain, GO:0001934). Inflammatory pathways with complement components (inflammatory response, GO:0006954) and cytokines (chemotaxis, GO:0042330) were strongly up-regulated in insulin-resistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia. Furthermore, differences were observed in genes contributing to fatty acid, cholesterol and triglyceride metabolism (FATP2, ELOVL6, PNPLA3, SREBF1) and in genes involved in regulating lipolysis (ANGPTL4) between the insulin-resistant and -sensitive subjects especially during hyperinsulinemia.
The major finding of this study was lower expression of mitochondrial respiratory pathway and defective induction of lipid metabolism pathways by insulin in insulin-resistant subjects. Moreover, the study reveals several novel genes whose aberrant regulation is associated with the obese insulin-resistant phenotype.