Protective effects of cyanidin-3-O-glucoside against lipotoxicity in hypertrophic adipocytes

Obesity is a metabolic disorder of multifactorial origin correlated with an elevated morbidity and mortality rates. It predisposes to the metabolic syndrome and is characterized by excess adipose tissue, altered levels of circulating proinflammatory adipokines, imbalances of the adaptive immune system and local and systemic chronic inflammation. In particular, obesity is associated with a state of "chronic low-grade inflammation", which plays an important pathophysiological role in the development and progression of many chronic pathologies, such as insulin resistance, endothelial dysfunction and dyslipidemia. Furthermore lipotoxicity, common in the adipose tissue, contributes to exacerbate the problems associated with these pathological conditions. FFA, including palmitic acid (PA), are in fact considered among the main causes of the onset of inflammation and insulin resistance in the adipose tissue. In recent years, epidemiological evidences have shown that anthocyanins, natural phenols commonly present in food and vegetables from Mediterranean Diet possesses not only a high antioxidant and anti-inflammatory activity, but also a marked anti-obesity and insulin sensitizing effect. Therefore, the aim of this work was to evaluate the potential beneficial effects of cyanidin-3-O-glucoside (C3G) in counteracting the inflammatory condition and the insulin resistance induced by high concentrations of PA at the adipose tissue level, through the use of an in vitro experimental models on murine (3T3-L1) and human (SGBS) adipocytes. In all experiments fully differentiated 3T3-L1 and SGBS adipocytes were pretreated with different concentrations of C3G for 24 h and then exposed to high concentrations of PA for further 24 h in order to induce cellular hypertrophy. To evaluate the insulin resistance condition, cells were subsequently treated with insulin. In particular, to characterize the effect of PA on the inflammatory process and the insulin resistance at molecular level and to demonstrate the protective effect of C3G in such conditions, for 3T3-L1 cells, we evaluated cellular signal pathways involved in adipogenesis (PPAR-γ pathway), inflammatory process (NF-kB pathway) and insulin resistance (IRS-1/PI3K/Akt pathway). Instead, in order to confirm the effects on human SGBS cells we assessed the mRNA levels of the main cytokines modulated by NF-kB (TNF-α, IL-6, IL-8, and MCP-1), and GLUT-1, GLUT-4, hexokinase and adiponectin as markers of insulin sensitivity. Data reported in this thesis demonstrate that C3G ameliorates inflammation and insulin resistance conditions induced by PA, thus suggesting new potential roles for this natural compound in the prevention and treatment of pathological conditions linked to obesity.