Effect of BM 17.0744, a PPARalpha ligand, on the metabolism of perfused hearts from control and diabetic mice.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates the expression of fatty acid (FA) oxidation genes in liver and heart. Although PPARalpha ligands increased FA oxidation in cultured cardiomyocytes, the cardiac effects of chronic PPARalpha ligand administration in vivo have not been studied. Diabetic db/db mouse hearts exhibit characteristics of a diabetic cardiomyopathy, with altered metabolism and reduced contractile function. A testable hypothesis is that chronic administration of a PPARalpha agonist to db/db mice will normalize cardiac metabolism and improve contractile function. Therefore, a PPARalpha ligand (BM 17.0744) was administered orally to control and type 2 diabetic (db/db) mice (37.9 +/- 2.5 mg/(kg.d) for 8 weeks), and effects on cardiac metabolism and contractile function were assessed. BM 17.0744 reduced plasma glucose in db/db mice, but no change was observed in control mice. FA oxidation was significantly reduced in BM 17.0744 treated db/db hearts with a corresponding increase in glycolysis and glucose oxidation; glucose and FA oxidation in control hearts was unchanged by BM 17.0744. PPARalpha treatment did not alter expression of PPARalpha target genes in either control or diabetic hearts. Therefore, metabolic alterations in hearts from PPARalpha-treated diabetic mice most likely reflect indirect mechanisms related to improvement in diabetic status in vivo. Despite normalization of cardiac metabolism, PPARalpha treatment did not improve cardiac function in diabetic hearts.