GW-501516, also known as, Cardarine, is a peroxisome proliferator-activator receptor-delta agonist (PPARδ). GW501516 has been investigated for the treatment of Obesity, Lipid Disorders, and Cardiovascular Disease. A reduction in fatty acid (FA) oxidation has been associated with lipid accumulation and insulin resistance in skeletal muscle of obese individuals. Numerous reports suggest that the reduction in FA oxidation may result from intrinsic mitochondrial defects. It was concluded that the reduced FA oxidation in obesity is attributable to decreased muscle mitochondrial content and not intrinsic defects in mitochondrial FA oxidation and that mitochondrial FAT/CD36 is involved in regulating FA oxidation in human skeletal muscle. The reduced skeletal muscle mitochondrial content with obesity may result from impaired mitochondrial biogenesis. Cell culture experiments revealed the protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression.
Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF. 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 PPARdelta 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. Skeletal muscle dysfunction in HF (heart failure) is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA (fatty acid) metabolism and improves exercise capacity in mice with LV (left ventricular) dysfunction.
- Significant reductions in fasting plasma triglycerides (-30%), apolipoprotein
B (-26%), LDL cholesterol (-23%), and insulin (-11%)
- Enhances the specific consumption of fatty acids and reducing glucose utilization
- Improved HDLc and triglyceride levels in healthy volunteers
- Upregulates skeletal muscle peroxisome proliferator-activated receptor (PPAR)delta expression
- Improved in vivo serum fat clearance, and the first demonstrated in vitro upregulation in human skeletal muscle fat utilization and ABCA1 expression
- PPARdelta agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle
- Induced FAO (fatty acid oxidation) and upregulated CPT1 and CD36 expression