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

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) regulates the expression of fatty acid (FA) oxidation genes in liver and heart. Although PPARa ligands increased FA oxidation in cultured cardiomyocytes, the cardiac effects of chronic PPAR alpha 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 PPAR alpha agonist to db/db mice will normalize cardiac metabolism and improve contractile function. Therefore, a PPAR alpha 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. PPAR alpha treatment did not alter expression of PPAR alpha target genes in either control or diabetic hearts. Therefore, metabolic alterations in hearts from PPAR alpha-treated diabetic mice most likely reflect indirect mechanisms related to improvement in diabetic status in vivo. Despite normalization of cardiac metabolism, PPAR alpha treatment did not improve cardiac function in diabetic hearts.