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Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor- transgenic mice

¹Departments of Pharmacology and Pediatrics, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and ²Division of General and Developmental Medicine, Department of Diabetes and Metabolic Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 4NS United Kingdom

Submitted 30 September 2002 ; accepted in final form 14 March 2003

The pyruvate dehydrogenase enzyme complex (PDC) is rate limiting for glucose oxidation in the heart. Inhibition of PDC by end-product feedback and phosphorylation by pyruvate dehydrogenase kinase (PDK) operate in concert to inhibit PDC activity. Because the transcriptional regulator peroxisome proliferator-activated receptor (PPAR)- increases PDK expression in some tissues, we examined what role PPAR- has in regulating glucose oxidation in hearts from mice overexpressing PPAR- (MHC-PPAR- mice). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPAR- mice compared with wild-type littermates (428 ± 113 vs. 771 ± 63 nmol · g dry weight^-1 · min^-1, respectively), which was accompanied by a parallel increase in fatty acid oxidation. However, there was no difference in PDC activity between MHC-PPAR- and wild-type animals, even though the expression of the PDK isoform PDK1 was increased in MHC-PPAR- mice. Glucose oxidation rates in both MHC-PPAR- and wild-type mouse hearts were decreased after 48-h fasting (which increases PPAR- expression) or by treatment of mice with the PPAR- agonist WY-14,643 for 1 wk. Despite this, PDC activity in both animal groups was not altered. Taken together, these data suggest that glucose oxidation rates in the heart can be dramatically altered independent of PDK phosphorylation and inhibition of PDC by PDK. It also suggests that PPAR- activation decreases glucose oxidation in hearts mainly by decreasing the flux of pyruvate through PDC due to negative feedback of PDC by fatty acid oxidation reaction products rather than by the phosphorylated state of the PDC complex.

glucose oxidation; fatty acid oxidation; pyruvate dehydrogenase kinase

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