Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

TLDR

The study aimed to determine how PPARδ regulates metabolic homeostasis by employing subtype‑selective agonists. Using the selective agonist GW501516, the authors examined PPARδ‑dependent transcriptional changes in rat L6 myotubes and mouse skeletal muscle, focusing on genes governing fatty‑acid transport, β‑oxidation, and mitochondrial respiration. Activation of PPARδ by GW501516 upregulated genes for fatty‑acid transport, β‑oxidation, and mitochondrial respiration, increased fatty‑acid oxidation in muscle, and ameliorated high‑fat‑diet–induced obesity, insulin resistance, and hyperglycemia in mice, including ob/ob animals.

Abstract

In this study, we defined the role of peroxisome proliferator-activated receptor β/δ (PPARδ) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARδ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARδ controls fatty acid oxidation by regulating genes involved in fatty acid transport, β-oxidation, and mitochondrial respiration. Similar PPARδ-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid β-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid β-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob / ob mice. These data suggest that PPARδ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.