Author:

Keywords:

Obesity, Metabolic syndrome, Cardiovascular diseases, Inflammation, Oxidative stress, Monocytes, Biomarker, microRNA

Abstract:

Cardiovascular diseases (CVD) are still the main cause of mortality and morbidity worldwide. This can be explained by the increasing prevalence of obesity and type 2 diabetes. The risk of developing CVD is directly related to the concomitant burden of obesity-related risk factors clustered in the metabolic syndrome: dyslipidemia, hyperglycemia and insulin resistance, and hypertension. Indeed, increased inflammation and oxidative stress associated with obesity play a central role in the development of obesity-induced metabolic disorders such as metabolic syndrome, type 2 diabetes and atherosclerosis. However, the underlying cellular and molecular mechanisms that link these processes remain to be elucidated. Therefore, the aim of this dissertation is to unravel the mechanisms of inflammation and oxidative stress during obesity and associated metabolic disorders.First, we discuss cellular and molecular mechanisms explaining the existence of a vicious circle between inflammation and oxidative stress in obese adipose and atherosclerotic vascular tissues. Inflammatory cells like monocytes and macrophages play a significant role in initiating the inflammatory cascade leading to enhanced oxidative stress. The enhanced oxidative stress, at its turn, increases the infiltration of inflammatory cells emphasizing the existence of a vicious circle. Moreover, circulating monocytes are already activated in obese individuals and are characterized by an increased inflammatory and oxidative stress state. Since these peripheral blood cells are easily accessible, gene expression analysis in circulating monocytes could yield valuable biomarkers that may reflect presence and activity of obesity-associated metabolic disorders.Second, we identify a cluster of genes that connects chronic inflammation with oxidative stress in circulating monocytes of obese individuals before infiltrating adipose or vascular tissues. IRAK3 is the only downregulated inhibitor of this gene cluster in obese monocytes. Low IRAK3 is associated with high SOD2, a marker of mitochondrial oxidative stress. Interestingly, the combination of low IRAK3 and high SOD2 is the strongest predictor of metabolic syndrome; it is even stronger than C-reactive protein. In addition, we identify the increase in oxidative stress in combination with obesity-associated low adiponectin as cause of the decrease in IRAK3.Third, we discuss the involvement of regulating microRNAs (miRs) in the increased inflammatory and oxidative stress state associated with obesity and related metabolic disorders. Hereby, we review miRs that share similar expression profiles in the diseased tissues during obesity and atherosclerosis. These common miRs regulate molecules related to processes that play a role in the development of obesity-associated diseases, and may be especially useful targets for treatment.Fourth, we identify several differentially expressed miRs in circulating monocytes of obese individuals that are involved in the regulation of the IRAK3-related cluster and are associated with metabolic syndrome and CVD. For example, we identify miR-146b-5p as downregulated miR with validated targets in the IRAK3-related gene cluster and as major mediator of the anti-inflammatory action of adiponectin on monocytes. miR-181a is also downregulated in monocytes of obese patients and an in silico analysis identifies several molecules in the IRAK3-related gene cluster as putative targets. Interestingly, miR-181a predicts a higher number of metabolic syndrome components and is associated with the occurrence of coronary artery disease even after adjustment for traditional risk factors, obesity and the metabolic syndrome.To conclude we identify a gene/miR signature in monocytes of obese patients with interesting perspectives for risk stratification for the prevention and treatment of obesity-associated metabolic disorders. Early detection of obese individuals at highest risk of developing co-morbidities makes it possible to present these patients with the best treatment option to attenuate their risk and associated mortality rate.