Adipose tissue dysfunction and cardiometabolic risk. Ex vitro, in vivo and clinical studies

While the obesity epidemic develops at an alarming rate, scientifically we are still far behind with regard to diagnostic and therapeutic actions. In this thesis, we aimed to explore current and novel pathways in adipose tissue dysfunction, as a result of obesity, and investigated how they might contribute to metabolic and cardiovascular disease. In chapter 2, current knowledge of pathophysiological mechanisms linking abdominal adipose tissue to obesity-related metabolic dysfunction is reviewed, with a special focus on distinct adipose tissue depots and the role of adipose tissue-derived extracellular vesicles. Adipose tissue consists of different depots which are anatomically linked to distinct organs. Evidence suggests that intrinsic differences as well as interactions of adipose tissue with surrounding organs accounts for different contributions to cardiometabolic disease. In chapter 3 we explored the inflammatory profile of four different abdominal adipose tissue depots and their relation with parameters of metabolic dysfunction in a clinical study considering abdominally lean versus abdominally obese male patients. The most striking finding was the differential contribution of distinct visceral fat depots with metabolic dysfunction. Mesenteric fat morphology was mainly related to insulin resistance, whereas omental fat morphology was more strongly related to higher triglyceride and lower HDL-cholesterol levels. Extracellular vesicles (EVs) are active signaling vesicles important for communication between cells. In obesity, communication between adipocytes and immune cells such as macrophages is a key mechanism in adipose tissue inflammation, leading to metabolic complications like insulin resistance. In chapter 4 we have shown that EVs released by human in vitro differentiated adipocytes or ex vivo human adipose tissue explants can stimulate macrophages which subsequently induced insulin resistance in in vitro differentiated adipocytes. Furthermore, EVs of visceral but not subcutaneous adipose tissue were also quantitatively related to systemic insulin resistance. In chapter 5 we have shown that adiponectin-positive EVs were isolated from human plasma suggesting secretion of EVs into the circulation enabling endocrine signaling of fat EVs. Adipose tissue EVs, derived from ex vivo human fat explants, could inhibit insulin signaling in liver cells in vitro, which was related to pro-inflammatory adipokines present in EVs of visceral adipose tissue. In chapter 6, we have explored the potential of EV-associated markers, associated with cardiovascular disease, to serve as biomarkers for obesity-induced metabolic disease in patients with manifest cardiovascular disease. EV-cystatin C levels were positively related to metabolic complications of obesity. In contrast, EV-CD14 levels were inversely related to visceral obesity in males and associated with a relative risk reduction for the development of type 2 diabetes, indicating that EV-CD14 might be a protective biomarker for obesity-induced metabolic disease. In chapter 7, the potential prognostic value of adiponectin, an adipocyte specific marker with insulin sensitizing properties, as biomarker for cardiovascular disease is studied in a meta-analysis, which showed no relation between circulating levels of adiponectin and incident CHD or stroke. Therefore, despite all metabolic beneficial properties of adiponectin observed in vivo or in vitro, systemic levels of adiponectin do not seem to cover enough of the underlying pathological activity to be used as a biomarker for obesity-induced cardiovascular disease. Exploiting the composition of adipose tissue EVs would enable multi-parameter biomarker development which seems crucial for complex diseases such as obesity-induced cardiometabolic disease. Furthermore, manipulation of the contents and binding specificity of adipose tissue-EVs hold true therapeutic potential for targeted delivery in vivo.