Abstract
BackgroundThe metabolic syndrome is becoming increasingly prevalent in the general population that is at simultaneous risk for both type 2 diabetes and cardiovascular disease. The critical pathogenic mechanisms underlying these diseases are obesity-driven insulin resistance and atherosclerosis, respectively. To obtain a better understanding of molecular mechanisms involved in pathogenesis of the metabolic syndrome as a basis for future treatment strategies, studies considering both inherent risks, namely metabolic and cardiovascular, are needed. Hence, the aim of this study was to identify pathways commonly dysregulated in obese adipose tissue and atherosclerotic plaques.MethodsWe carried out a gene set enrichment analysis utilizing data from two microarray experiments with obese white adipose tissue and atherosclerotic aortae as well as respective controls using a combined insulin resistance-atherosclerosis mouse model.ResultsWe identified 22 dysregulated pathways common to both tissues with p values below 0.05, and selected inflammatory response and oxidative phosphorylation pathways from the Hallmark gene set to conduct a deeper evaluation at the single gene level. This analysis provided evidence of a vast overlap in gene expression alterations in obese adipose tissue and atherosclerosis with Il7r, C3ar1, Tlr1, Rgs1 and Semad4d being the highest ranked genes for the inflammatory response pathway and Maob, Bckdha, Aldh6a1, Echs1 and Cox8a for the oxidative phosphorylation pathway.ConclusionsIn conclusion, this study provides extensive evidence for common pathogenic pathways underlying obesity-driven insulin resistance and atherogenesis which could provide a basis for the development of novel strategies to simultaneously prevent type 2 diabetes and cardiovascular disease in patients with metabolic syndrome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0441-2) contains supplementary material, which is available to authorized users.
Highlights
The metabolic syndrome is becoming increasingly prevalent in the general population that is at simultaneous risk for both type 2 diabetes and cardiovascular disease
Atherosclerotic plaque formation as analyzed by en-face staining revealed markedly enhanced atherosclerotic lesions in Ldlr−/− mice fed with diabetogenic diet (DDC) (Fig. 1c, d)
Together these results point to the simultaneous development of considerable obesity and atherosclerosis in Ldlr−/− mice fed with DDC used in this study, reflecting published findings in this mouse model
Summary
The metabolic syndrome is becoming increasingly prevalent in the general population that is at simultaneous risk for both type 2 diabetes and cardiovascular disease. The metabolic syndrome is a worldwide public health challenge with a prevalence above 20 % within adults in Western societies [1] This disorder is based on several factors including visceral obesity, hypertension, dyslipidemia and hyperglycemia conferring a fivefold increased risk for type 2 diabetes and twofold for cardiovascular disease compared to the non-affected population [2, 3]. Gene set enrichment analysis (GSEA) provides the possibility to compare data with different gene set databases of interest and reports group of genes associated with the same biological function or common pathways [12, 13] Such analyses allow a more general picture on dysregulation compared to analyses focusing on individual genes
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