Role of AMPK and PPARγ1 in exercise-induced lipoprotein lipase in skeletal muscle.

Exercise can effectively ameliorate type 2 diabetes and insulin resistance. Here we show that the mRNA levels of one of peroxisome proliferatoractivated receptor (PPAR) family members, PPARα1, and genes related to energy metabolism, including PPARα coactivator-1 protein- 1α (PGC-1α) and lipoprotein lipase (LPL), increased in the gastrocnemius muscle of habitual exercise-trained mice. When mice were intraperitoneally administered an AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), the mRNA levels of the aforementioned three genes increased in gastrocnemius muscle. AICAR treatment to C2C12 differentiated myotubes also increased PPARα1 mRNA levels, but not PPARα and -γ mRNA levels, concomitant with increased PGC-1α mRNA levels. An AMPK inhibitor, compound C, blocked these AICAR effects. AICAR treatment increased the half-life of PPARα1 mRNA nearly threefold (4-12 h) by activating AMPK. When C2C12 myoblast cells infected with a PPARα1 expression lentivirus were differentiated into myotubes, PPARα1 overexpression dramatically increased LPL mRNA levels more than 40-fold. In contrast, when PPARα1 expression was suppressed in C2C12 myotubes, LPL mRNA levels were significantly reduced, and the effect of AICAR on increased LPL gene expression was almost completely blocked. These results indicated that PPARα1 was intimately involved in LPL gene expression in skeletal muscle and the AMPK-PPARα1 pathway may play a role in exercise-induced LPL expression. Thus, we identified a novel critical role for PPARα1 in response to AMPK activation for controlling the expression of a subset of genes associated with metabolic regulation in skeletal muscle. [ABSTRACT FROM AUTHOR]