Roles of PPARΔ in the control of muscle development and metabolism

PPAR δ (peroxisome proliferator-activated receptor δ)-specific agonists decrease plasma lipids and insulinaemia in obese animals. As skeletal muscle is one of the major organs for fatty acid catabolism, we have investigated the roles of the nuclear receptor in the control of muscle development and lipid metabolism, by using two approaches. We have used C₂C₁₂ myotubes in which the PPAR δ activity was altered by overexpression of either native or dominant-negative (DN) mutant forms of PPAR δ. Treatment of C₂C₁₂ cells by specific PPAR δ agonists promotes expression of genes for proteins of fatty acid catabolism and increases fatty acid oxidation. These responses were increased in C₂C₁₂-PPAR δ cells and impaired in C₂C₁₂-PPAR δDN cells. We also constructed animal models with muscle-specific expression of PPAR δ (Cre/Lox approach). The effects of muscle-specific alteration of PPAR δ activity were studied on muscle development and metabolism as well as on body fat mass. These experiments indicated that PPAR δ plays a crucial role in myofibre typing determination and regulation of muscle oxidative capabilities, and that muscle-specific overexpression of the nuclear receptor leads to reduction of adipocyte size and body fat mass. These data strongly suggest that PPAR δ controls fatty acid catabolism in muscle and that its activation by synthetic agonists could prevent or correct obesity and type 2 diabetes.