Adipocyte dysfunction: modulation of weight loss associated miR

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Increasing prevalence of the metabolic syndrome (MetS) represents a major public health burden. The underlying mechanism involves obesity associated metabolically stressed adipocytes and accumulation of proinflammatory macrophages in adipose tissue. Interaction between proinflammatory macrophages and lipid laden adipocytes is suggested to contribute to adipose tissue dysfunction and to promote local insulin resistance, lipid spillover and systemic low-grade inflammation.So far, lifestyle-induced weight loss is regarded as efficient therapy to ameliorate MetS and to prevent type 2 diabetes and CVD in individuals with MetS. However, information about the molecular pathways that promote reversibility of adipocyte dysfunction in patients with MetS is scarce at best. Adipocytes and adipose tissue macrophages react to weight loss by alterations of cell specific gene expression, which is regulated by microRNA´s (miR). Hence, modulation of adipose and macrophage specific miR expression may represent a molecular target to improve adipose tissue dysfunction in individuals with MetS. To identify weight loss associated miR, we analyzed mRNA and miR expression in subcutaneous adipose tissue of individuals with MetS. 74 non-smoking, non-diabetic men aged between 45 and 55 years with MetS as defined by the International Diabetes Federation guidelines were randomized to a 6 months tele-monitored lifestyle-induced weight loss intervention group or to a control arm. First results of this study were already published by us in 2016 (Scientific Reports, Nature Publishing Group). By paired analysis we identified 7 miR that were differently regulated following lifestyle-induced weight loss. Target prediction analysis revealed that two specific miR have potential binding sites in differently regulated genes that can be predominantly clustered by function for lipid metabolism and for macrophage activity. We now aim to exploit these data to ascertain whether modulation of the identified weight loss associated miR regulate adipocyte function in regard to adipogenesis, ROS production, insulin sensitivity, macrophage differentiation, macrophage activation and adipocyte-macrophage interaction. As mouse orthologues exist only for a subset of identified miR and as species differences in regard to the pathophysiological mechanisms underlying MetS and lifestyle induced gene expression are highly likely, we will analyze the function of identified miR on adipocytes and macrophages using human in vitro models. With this approach we hope to identify new pathways ameliorating obesity related adipocyte dysfunction.The following goals will be investigated:Goal 1a: Impact of HSA-miR-548y on adipocyte VLDL uptakeGoal 1b: Impact of HSA-miR-548y on macrophage differentiation and activation Goal 2: Impact of identified miR on adipocyte differentiation, ROS production and insulin sensitivityGoal 3: Impact of identified miR on adipocyte-macrophage interaction