Journal
FEBS JOURNAL
Volume 279, Issue 10, Pages 1883-1893Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1742-4658.2012.08569.x
Keywords
clofibric acid; diet-induced obesity; peroxisome proliferator-activated receptor a; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
Categories
Funding
- National Institutes of Health [DK47844]
- VA Merit Review Grant
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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 a (PPARa) agonists are often used to treat dyslipidemia in patients, especially in type 2 diabetes. Combinational treatment using a PDK4 inhibitor and PPARa agonists may prove beneficial. However, PPARa agonists may be less effective in the presence of a PDK4 inhibitor because PPARa agonists induce PDK4 expression. In the present study, the effects of clofibric acid, a PPARa 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.
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