The role of PPARs in inflammation and obesity

As the number of obese individuals worldwide keeps rising steadily, a global epidemic of obesity-related complications is on the horizon. Obesity greatly increases the risk for cardiovascular disease and Type II diabetes, especially when excess body fat is present in and around the abdomen. To prevent the obesity epidemic from getting completely out of control, effective strategies to reduce the incidence of obesity are urgently needed. Seemingly, obesity can be easily treated or prevented by reducing food intake and increasing physical activity levels. However, the low success rate of these strategies together with the prospect of potential huge financial rewards has shifted the emphasis to pharmalogical approaches to reverse obesity and obesity-related complications. One important group of molecular targets for the treatment of obesity and related disorders are the Peroxisome Proliferator Activated Receptors ( PPARs ), a group of ligand -activated transcription factors that consists of three members: PPARα, PPARβ/δ and PPARγ. Each PPAR governs the expression of specific sets of target genes involved in various cellular processes ranging from inflammation to glucose and lipid metabolism. Currently, synthetic agonists for PPARs are prescribed for the treatment of dyslipidemia and insulin resistance. Apart from metabolic abnormalities, obesity is also accompanied by a chronic low grade inflammation, which is generally believed to originate from expanding adipose tissue. Elevated secretion of pro-inflammatory factors from adipose tissue has been linked to the development of atherosclerosis and insulin resistance. Since PPARs have important anti-inflammatory properties in a wide variety of cell types, they might protect against obesity-induced inflammation and its complications. Although the PPARα isotype is known to suppress inflammation, relatively little is known about the specific inflammatory pathways that are governed by PPARα in liver. By using microarray analysis, we compared the expression profiles of inflamed and PPARα-activated liver. Whereas inflammation up-regulated numerous pro-inflammatory genes, activation of PPARα in liver resulted in an opposite expression profile. We were able to identify interleukin receptor 1 antagonist, which suppresses the effect of IL-1, as a direct target gene of PPARα. To investigate whether PPARα is involved in controlling obesity-induced inflammation, both Wildtype and PPARα -/- mice were fed either a low fat diet or a high fat diet. After the diet intervention, liver gene expression profiles were compared by microarray analysis. In Wildtype mice, HFD significantly increased the hepatic and adipose expression of numerous genes involved in inflammation. Importantly, this effect was amplified in PPARα-/- mice, suggesting an anti-inflammatory role of PPARα in liver and adipose tissue. Further studies were carried out to investigate the mechanism behind the anti-inflammatory role of PPARα. These studies led to the conclusion that PPARα protects against obesity-induced chronic inflammation in liver by reducing hepatic steatosis , by direct down-regulation of inflammatory genes, and by attenuating inflammation in adipose tissue. PPARγ is highly expressed in adipose tissue and has therefore been extensively studied in the context of obesity. However, less is known about the impact of PPAR g on obesity-induced inflammation. Accordingly, we tested whether activation of PPARγ by rosiglitazone could reverse the inflammatory status of adipose tissue observed in obese mice. PPARγ activation resulted in suppression of pro-inflammatory gene expression and led to remodeling of adipose tissue. Surprisingly, the number of macrophages in adipose tissue was increased after rosiglitazone treatment. However, gene expression changes obtained via qPCR analysis suggested that these macrophages were alternatively activated and might contribute to cell proliferation and remodeling of the adipose tissue. Finally, the last part of this thesis describes the identification of Glycogen Synthase 2, the rate-limiting enzyme in the conversion of glucose to glycogen, as a novel PPAR target gene in liver and adipose tissue. The complexity of regulation by the hepatocyte nuclear factor 4α and PPARs via different response elements is shown.