Genetic and nutritional studies to elucidate the role of adipose tissue in the pathogenesis of metabolic syndrome

Obesity is a major health problem in the United States and worldwide. It increases the risk for type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in white adipose tissue (WAT) is causally linked to the development of insulin resistance (IR), metabolic syndrome and obesity-associated chronic diseases. The aim of this dissertation research was to elucidate the WAT function in metabolic syndrome using genetic (overexpression of an adipose pro-inflammatory hormone, angiotensinogen) and nutritional manipulations/approaches (caloric restriction and omega-3 fatty acids), with specific emphasis on the role of inflammation.

Previous research indicates that WAT renin-angiotensin system (RAS) is overactivated in obesity. However, its role in the pathogenesis of IR is hitherto unknown. Using mice overexpressing angiotensinogen (Agt), the only precursor for the hypertensive hormone angiotensin (Ang) II, in WAT, we showed that adipose-specific RAS overactivation leads to systemic IR. This is at least in part due to Ang II, NADPH oxidase and NF-kB-dependent increases in WAT inflammation.

Caloric restriction is the main dietary intervention to treat obesity-associated metabolic disorders. While most health agencies recommend a low-fat diet, energy-restricted high-fat diets (HFR) are also claimed to be effective in this regard. Here, we show that weight loss due to HFR is accompanied by improvements of IR but only partial resolution of WAT inflammation. Further, this diet negatively impacted the adipokine profile supporting the current recommendations for low-fat diets.

Dietary interventions targeted at reducing WAT inflammation have not been explored in detail. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid of marine origin with anti-inflammatory properties. We show that EPA is able to both prevent and reverse high-fat diet-induced IR and hepatic steatosis via modulation of WAT inflammation.

In conclusion, primary changes occurring in WAT, such as overexpression of Agt, can lead to WAT inflammation and systemic IR. Moreover, nutritional interventions targeting at reducing adiposity (caloric restriction) and inflammation (EPA) can both lead to improvements in systemic IR. Our findings support the current recommendation of low-fat diets for improvement in metabolic profile and show that dietary modulation of WAT function can be used to improve metabolic derangements in obesity.