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 proliferator-activated receptor (PPAR) family members, PPAR gamma 1, and genes related to energy metabolism, including PPAR gamma coactivator-1 protein-1 alpha (PGC-1 alpha) 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 PPAR gamma 1 mRNA levels, but not PPAR alpha and -delta mRNA levels, concomitant with increased PGC-1 alpha mRNA levels. An AMPK inhibitor, compound C, blocked these AICAR effects. AICAR treatment increased the half-life of PPAR gamma 1 mRNA nearly threefold (4-12 h) by activating AMPK. When C2C12 myoblast cells infected with a PPAR gamma 1 expression lentivirus were differentiated into myotubes, PPAR gamma 1 overexpression dramatically increased LPL mRNA levels more than 40-fold. In contrast, when PPAR gamma 1 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 PPAR gamma was intimately involved in LPL gene expression in skeletal muscle and the AMPK-PPAR gamma 1 pathway may play a role in exercise-induced LPL expression. Thus, we identified a novel critical role for PPAR gamma 1 in response to AMPK activation for controlling the expression of a subset of genes associated with metabolic regulation in skeletal muscle.