Although improving
glucose metabolism by inhibition of
pyruvate dehydrogenase kinase 4 (PDK4) may prove beneficial in the treatment of
type 2 diabetes or diet-induced
obesity, it may have detrimental effects by inhibiting
fatty acid oxidation.
Peroxisome proliferator-activated receptor α (PPARα) agonists are often used to treat
dyslipidemia in patients, especially in
type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARα agonists may prove beneficial. However, PPARα agonists may be less effective in the presence of a PDK4 inhibitor because PPARα agonists induce PDK4 expression. In the present study, the effects of
clofibric acid, a PPARα agonist, on blood and liver
lipids were determined in wild-type and PDK4 knockout mice fed a high-fat diet. As expected, treatment of wild-type mice with
clofibric acid resulted in less
body weight gain, smaller epididymal fat pads, greater
insulin sensitivity, and lower levels of serum and liver
triacylglycerol. Surprisingly, rather than decreasing the effectiveness of
clofibric acid, PDK4 deficiency enhanced the beneficial effects of
clofibric acid on hepatic steatosis, reduced
blood glucose levels, and did not prevent the positive effects of
clofibric acid on serum
triacylglycerols and
free fatty acids. The metabolic effects of
clofibric acid are therefore independent of the induction of PDK4 expression. The additive beneficial effects on hepatic steatosis may be due to induction of increased capacity for
fatty acid oxidation and partial uncoupling of oxidative phosphorylation by
clofibric acid, and a reduction in the capacity for
fatty acid synthesis as a result of PDK4 deficiency.