Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart

In the diabetic heart, chronic activation of the PPARα pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPARβ/δ, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPARβ/δ, driven by the myosin heavy chain (MHC-PPARβ/δ mice). In striking contrast to MHC-PPARα mice, MHC-PPARβ/δ mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARα but not by PPARβ/δ. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPARβ/δ mice, but repressed in MHC-PPARα mice. In reporter assays, we showed that PPARβ/δ and PPARα exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARβ/δ mice compared with control or MHC-PPARα mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPARα and PPARβ/δ drive distinct cardiac metabolic regulatory programs and identify PPARβ/δ as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia

The nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2

Efficient cellular energy metabolism is critical for optimal muscle performance and fitness. Kelly and colleagues describe a novel regulatory pathway that reprograms muscle energy metabolism to resemble an exercise-trained phenotype. Using PPARβ/δ transgenic mice, they identify a PPARβ/δ-specific transcriptional program that increases the expression of lactate dehyrogenase B (LDHB). This results in the diversion of glycolytic end products into the mitochondrion for complete oxidation and ATP generation. The PPARβ/δ transgenic mice thus persistently oxidize glucose and exhibit increased endurance. This study provides valuable insight into the regulation of muscle glucose utilization as well as into pathways regulating obesity and diabetes