Abstract
BackgroundTo 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.MethodsSubcutaneous 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.ResultsThe 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.ConclusionsThe 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.
Highlights
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
Expression of sterol regulatory element binding transcription factor 1 (SREBF1) and its target hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) displayed significantly lower mRNA levels in the insulinresistant group after 3 h (p < 0.05 and p < 0.001) and 6 h (p < 0.05 for both genes) of hyperinsulinemia (Figure 5E &5F). The expression of both SREBF1 (p < 0.001 at 6 h for insulin-sensitive, p < 0.01 for insulin-resistant) and Discussion In the present study we compared the acute in vivo effects of insulin on adipose tissue transcriptional profiles of obese insulin-resistant and lean insulin-sensitive women, to gain insight into the molecular mechanisms underlying insulin resistance
Inflammatory pathways with complement components and cytokines were strongly up-regulated in insulinresistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia
Summary
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. A number of transcriptome studies have reported differences in adipose tissue mRNA expression at fasting state between obese and lean subjects (reviewed in [3]). Most of these investigations have been performed after an overnight fast [4,5,6,7,8,9,10,11,12,13,14] and they compare differences between obese and non-obese subjects [5,6,10,11,12,13,14], predominantly in males or mixed groups consisting of both males and females. Analysis of subcutaneous adipose tissue transcript profiles in monozygotic twins revealed elevated expression of several pro-inflammatory cytokines and complement components in the in the obese, insulin-resistant co-twins as compared to the non-obese ones [12]
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