PGC-1alpha-induced improvements in skeletal muscle metabolism and insulin sensitivity

The peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1alpha, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1alpha. Indeed, PGC-1alpha overexpression, like exercise training, increases exercise performance. PGC-1alpha reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1alpha mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1alpha overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1alpha, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1alpha was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1alpha-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1alpha overexpression, but not physiologic PGC-1alpha overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1alpha.