A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated receptors which regulate genes involved in lipid meta bolism and homeostasis. PPAR alpha is preferentially expressed in the liver and PPAR gamma preferentially in adipose tissue. Activation of PPAR alpha leads to peroxisome proliferation in rodents and increased beta-oxidation o f fatty acids. PPAR gamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both of these PPAR recept ors are potential targets for treatment of dyslipidemia in man. Studies by others using a proteomics approach have characterized the effects of PPAR a lpha agonists in livers from lean healthy mice. However, we wanted to map t he effects of a therapeutic dose of a PPAR alpha agonist in a disease model of insulin resistance and diabetes, the obese diabetic ob/ob mouse, by pro teomics. Therefore, ob/ob mice, which have highly elevated levels of plasma triglycerides, glucose and insulin, were treated for one week with WY14,64 3 (180 mu mol/kg/day), a well-characterized selective PPAR alpha agonist. P lasma triglycerides, glucose and insulin levels were determined and we foun d significant therapeutic effects on triglycerides and glucose levels. The liver protein compositions were investigated by high-resolution two-dimensi onal gel electrophoresis which showed that WY14,643 produced up-regulation of at least 16 spots. These were identified by mass spectrometry and 14 spo ts were found to be components of the peroxisomal fatty acid metabolism. Th us, WY14,643 at a therapeutic dose, caused induction of peroxisomal fatty a cid beta-oxidation in obese diabetic mice.