Improved Cardiac Metabolism Following in Vivo Treatment of Type 2 Diabetic Mice with Fenofibrate Depends on Reduction of Plasma Lipids, as Well as Glucose

Abstract

The plasma supply of energy substrates plays a key role in determining the cardiac metabolic phenotype. In diabetes, a high plasma supply of fatty acids (FA) leads to a predominant oxidation of FA for energy production, while glucose oxidation is markedly suppressed. The db/db mouse is a well accepted model of type 2 diabetes, showing hyperglycemia, hyperlipidemia, and hyperinsulinemia. Hearts from these mice exhibit altered substrate metabolism, characterized by an over-reliance on FA for energy production and low contribution of glucose. In the present study we tested whether the capacity for glucose utilization could be recovered in isolated working hearts from db/db mice following long-term (4 weeks) treatment with fenofibrate, using two different doses of the compound (0.1% and 0.2%, given as admixture to the diet). Mice treated with K-111 (a PPARα agonist, previously known as BM 17.0744) served as positive controls. In line with previous results, treatment with K-111 resulted in a significant reduction of the plasma concentrations of FA, triacylglycerol (TG) and glucose. Low-dose (0.1 %) fenofibrate treatment resulted in reduced plasma concentration of FA and TG, whereas the concentration of glucose was unaffected. With high-dose (0.2 %) fenofibrate, however, significant reductions of both lipids and glucose were obtained. Hearts from K-111-treated db/db mice showed a 74% decrease in FA oxidation and a near 2-fold increase in glucose oxidation. Treatment with low-dose fenofibrate failed to improve cardiac metabolism, whereas high-dose fenofibrate caused a similar shift in cardiac metabolism as seen with K-111. The alterations in cardiac metabolism were associated with changes in the myocardial and hepatic expression of PPARα-regulated target genes. These results indicate that reduction of plasma lipids alone is not sufficient for improving cardiac metabolism in diabetes, and that reduction of plasma glucose is also required.