Peroxisome proliferator-activated receptor ? decouples fatty acid uptake from lipid inhibition of insulin signaling in skeletal muscle.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is expressed at low levels in skeletal muscle, where it protects against adiposity and insulin resistance via unclear mechanisms. To test the hypothesis that PPAR? directly modulates skeletal muscle metabolism, we created two models that isolate direct PPAR? actions on skeletal myocytes. PPAR? was overexpressed in murine myotubes by adenotransfection and in mouse skeletal muscle by plasmid electroporation. In cultured myotubes, PPAR? action increased fatty acid uptake and incorporation into myocellular lipids, dependent upon a 154 ± 20-fold up-regulation of CD36 expression. PPAR? overexpression more than doubled insulin-stimulated thymoma viral proto-oncogene (AKT) phosphorylation during low lipid availability. Furthermore, in myotubes exposed to palmitate levels that inhibit insulin signaling, PPAR? overexpression increased insulin-stimulated AKT phosphorylation and glycogen synthesis over 3-fold despite simultaneously increasing myocellular palmitate uptake. The insulin signaling enhancement was associated with an increase in activating phosphorylation of phosphoinositide-dependent protein kinase 1 and a normalized expression of palmitate-induced genes that antagonize AKT phosphorylation. In vivo, PPAR? overexpression more than doubled insulin-dependent AKT phosphorylation in lipid-treated mice but did not augment insulin-stimulated glucose uptake. We conclude that direct PPAR? action promotes myocellular storage of energy by increasing fatty acid uptake and esterification while simultaneously enhancing insulin signaling and glycogen formation. However, direct PPAR? action in skeletal muscle is not sufficient to account for the hypoglycemic actions of PPAR? agonists during lipotoxicity.

SUBMITTER: Hu S 

PROVIDER: S-EPMC3355543 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other