Journal article
Peroxisome Proliferator-Activated Receptor γ Decouples Fatty Acid Uptake from Lipid Inhibition of Insulin Signaling in Skeletal Muscle
Molecular endocrinology (Baltimore, Md.), Vol.26(6), pp.977-988
06/01/2012
DOI: 10.1210/me.2011-1253
PMCID: PMC3355543
PMID: 22474127
Abstract
Abstract
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.
Details
- Title: Subtitle
- Peroxisome Proliferator-Activated Receptor γ Decouples Fatty Acid Uptake from Lipid Inhibition of Insulin Signaling in Skeletal Muscle
- Creators
- Shanming Hu - 1Departments of Pediatrics (S.H., J.Y., A.A.H., B.M.M., A.W.N.), Iowa City, Iowa 52242Jianrong Yao - 1Departments of Pediatrics (S.H., J.Y., A.A.H., B.M.M., A.W.N.), Iowa City, Iowa 52242Alexander A Howe - 1Departments of Pediatrics (S.H., J.Y., A.A.H., B.M.M., A.W.N.), Iowa City, Iowa 52242Brandon M Menke - 1Departments of Pediatrics (S.H., J.Y., A.A.H., B.M.M., A.W.N.), Iowa City, Iowa 52242William I Sivitz - 2Medicine (W.I.S.), Iowa City, Iowa 52242Arthur A Spector - 3Biochemistry (A.A.S.), University of Iowa, Iowa City, Iowa 52242Andrew W Norris - 1Departments of Pediatrics (S.H., J.Y., A.A.H., B.M.M., A.W.N.), Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Molecular endocrinology (Baltimore, Md.), Vol.26(6), pp.977-988
- Publisher
- Oxford University Press
- DOI
- 10.1210/me.2011-1253
- PMID
- 22474127
- PMCID
- PMC3355543
- ISSN
- 0888-8809
- eISSN
- 1944-9917
- Language
- English
- Date published
- 06/01/2012
- Academic Unit
- Endocrinology and Diabetes; Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024502902771
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