PPAR activation and mitochondrial function in obesity related diseases.

Disorders of lipid metabolism are intimately connected to many common, life-style related diseases. Obesity and obesity-related disorders, often referred to as the metabolic syndrome, is a serious condition with the presence of a number of risk factors li ke overweight, dyslipidaemia, hypertension and insulin resistance/type II diabetes. Obesity is a multi-factorial disease of complex aetiology. The amount of body fat is partly determined by genetic susceptibility, and partly by environmental factors. Whe n food intake chronically exceeds metabolic needs, excess energy is stored and results in obesity, a common condition associated with diabetes. The major treatment modalities for diabetes aim at lowering blood glucose levels by stimulating glucose upta ke in peripheral tissues. This further exacerbates insulin resistance when energy intake is in excess resulting in a vicious cycle. Therefore, novel therapies that promote increased energy expenditure are needed. We have hypothesized that dissipating exc ess energy through increased hepatic catabolism is a potential treatment strategy for obesity associated diabetes. There is a communication between liver, fat, muscle, and free fatty acids, and the metabolic syndrome is associated with elevated plasma triacylglycerol. Through studies in several animal models we have documented the importance of mitochondria for the lipid lowering effect of PPAR? ligands. In addition to the various PPAR isoforms (?,?,?), many nuclear receptor coactivator proteins have been identified in the past few years. Our knowledge of the molecular mechanisms that regulate the functions of these co-activators is limited. Our hypothesis is that PPAR?, ? and ? and their target genes are regulated differently in liver, skeletal m uscle and adipose tissue, and that extracellular signals modulates the transcriptional activity of PPAR via regulation of co-activator level and availability.