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

Mol Endocrinol. 2012 Jun;26(6):977-88. doi: 10.1210/me.2011-1253. Epub 2012 Apr 3.


Peroxisome proliferator-activated receptor γ (PPARγ) is expressed at low levels in skeletal muscle, where it protects against adiposity and insulin resistance via unclear mechanisms. To test the hypothesis that PPARγ directly modulates skeletal muscle metabolism, we created two models that isolate direct PPARγ actions on skeletal myocytes. PPARγ was overexpressed in murine myotubes by adenotransfection and in mouse skeletal muscle by plasmid electroporation. In cultured myotubes, PPARγ action increased fatty acid uptake and incorporation into myocellular lipids, dependent upon a 154 ± 20-fold up-regulation of CD36 expression. PPARγ 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, PPARγ 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, PPARγ overexpression more than doubled insulin-dependent AKT phosphorylation in lipid-treated mice but did not augment insulin-stimulated glucose uptake. We conclude that direct PPARγ action promotes myocellular storage of energy by increasing fatty acid uptake and esterification while simultaneously enhancing insulin signaling and glycogen formation. However, direct PPARγ action in skeletal muscle is not sufficient to account for the hypoglycemic actions of PPARγ agonists during lipotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism
  • Cell Line
  • Fatty Acids / metabolism
  • Glucose / metabolism
  • Glycogen / biosynthesis
  • Insulin / physiology*
  • Lipid Metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Oleic Acid / metabolism*
  • Oxidation-Reduction
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • PPAR gamma / physiology*
  • Phospholipids / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Rosiglitazone
  • Signal Transduction
  • Thiazolidinediones / pharmacology
  • Up-Regulation


  • CD36 Antigens
  • Fatty Acids
  • Insulin
  • PPAR gamma
  • Phospholipids
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Thiazolidinediones
  • Rosiglitazone
  • Oleic Acid
  • Glycogen
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose