title: Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A.
abstract: OBJECTIVE
  Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation.
  
  
  RESULTS
  We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt- and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine307phosphorylation - events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.
  
  
  CONCLUSIONS
  Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A.
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nardi
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lipina
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Magill
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, UMR-S 872, Paris, France; Université Pierre et Marie Curie - Paris 6, UMR-S 872, Paris, France; Université Paris Descartes, UMR-S 872, Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Hage Hassan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, UMR-S 872, Paris, France; Université Pierre et Marie Curie - Paris 6, UMR-S 872, Paris, France; Université Paris Descartes, UMR-S 872, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Hajduch
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gray
authors.affiliation: Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Hundal
mesh_terms: D000328:Adult; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000009:adverse effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D019787:Linoleic Acid / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology*; D019301:Oleic Acid / Q000494:pharmacology*; D010168:Palmitates / Q000009:adverse effects; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D007328:Insulin; D010168:Palmitates; D019301:Oleic Acid; D019787:Linoleic Acid; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054648:Protein Phosphatase 2