FFA uptake in combination with unaltered FFA incorporation into nonoxidative disposal in skeletal muscle and liver) surprised us based on our expectation that tesaglitazar should increase fatty acid oxidation capacity via PPARα activation suggested by previous studies showing tesaglitazar induced hepatic enlargement and upregulation of CYP4A [16, 17]. To further explore the specific potential of PPARα activation to enhance in vivo FFA oxidation we treated rats with a selective PPARα agonist, WY14,643. Despite a substantial (>2-fold increase) in ex vivo FFA oxidation capacity in the liver we detected no WY14,643 induced enhancement of in vivo FFA oxidation in the basal fasting situation or under conditions of substantially elevated oxidative metabolism induced by the uncoupler dinitrophenol (unpublished observations). On the basis of these results and our recent finding that plasma FFA oxidation is not reduced in obese compared to lean Zucker rats [33], it appears that levels of FFA oxidation, FFA oxidation capacity, and insulin resistance are independent, at least in this model. This is in contrast to the situation reported by some studies in insulin resistant humans where reduced fasting levels of whole body fatty acid oxidation are associated with impairment in skeletal muscle fatty acid oxidation capacity [4].
