Pyruvate dehydrogenase kinase isoform 4 (PDK4) is upregulated by starvation in many tissues of the body during starvation. This causes inactivation of the pyruvate dehydrogenase complex which blocks pyruvate oxidation and conserves lactate and alanine for gluconeogenesis. Enhanced PDK4 expression may be caused by the increase in free fatty acids that occurs during starvation. Free fatty acids can activate peroxisome proliferator-activated receptor a (PPAR alpha), and activation of PPAR alpha can promote PDK4 expression. This model is supported by the findings reported here that WY-14,643, a synthetic. PPAR alpha activator, increases PDK4 expression in wild-type mice but not in PPAR alpha -null mice. Starvation likewise increases the expression of PDK4 in tissues of wild-type mice but not in tissues of PPAR alpha -null mice. These findings document the functional importance of PPAR alpha for PDK4 expression during starvation and suggest an important role for elevated free fatty acids in the induction.