Peroxisome proliferator-activated receptor (PPAR) γ agonists, thiazolidinediones, are used for the treatment of type 2 diabetes [13], and PPARα agonists belonging to the fibrate class of compounds are used for the treatment of dyslipidemias [14]. Here we wanted to test the concept that a combined PPARα/γ agonist could improve metabolic flexibility in a widely used animal model of insulin resistance and dyslipidemia associated with obesity, the fa/fa Zucker rat. For this purpose we used tesaglitazar which binds and activates PPARα and PPARγ [15] and was under clinical investigation for its ability to correct disorders of glucose and lipid metabolism. We previously established that this agent increases whole body glucose metabolic insulin action in the obese Zucker rat [16, 17] but the tissue locus of this effect has not been reported. Using tracer methods, the present study provides a comprehensive insight into in vivo glucose and FFA fluxes, as well as, metabolic fate at the whole body and individual tissues levels. The results demonstrate both a profound metabolic inflexibility in the untreated obese Zucker rats compared with the lean control animals and a remarkable ability of tesaglitazar to restore insulin mediated fuel switching in these animals.
