High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells.
Obesity is a major risk factor for the development of insulin resistance, characterized by impaired stimulation of glucose disposal into muscle. The mechanisms underlying insulin resistance are unknown. Here we examine the direct effect of leptin, the product of the obesity gene, on insulin-stimulated glucose uptake in cultured rat skeletal muscle cells. Preincubation of L6 myotubes with leptin (2 or 100 nM, 30 min) had no effect on basal glucose uptake but reduced insulin-stimulated glucose uptake. However, leptin had no effect on the insulin-induced gain in myc-tagged glucose transporter 4 (GLUT4) appearance at the cell surface of L6 myotubes. Preincubation of cells with leptin also had no effect on insulin-stimulated tyrosine phosphorylation of insulin receptor, IRS-1 and IRS-2, phosphatidylinositol 3-kinase activity, or Akt phosphorylation. We have previously shown that insulin regulates glucose uptake via a signaling pathway sensitive to inhibitors of p38 MAP kinase. Here, leptin pretreatment reduced the extent of insulin-stimulated p38 MAP kinase phosphorylation and phosphorylation of cAMP response element binder, a downstream effector of p38 MAP kinase. These results show that high leptin levels can directly reduce insulin-stimulated glucose uptake in L6 muscle cells despite normal GLUT4 translocation. The mechanism of this effect could involve inhibition of insulin-stimulated p38 MAP kinase and GLUT4 activation.
Sweeney
G
G
Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
Keen
J
J
Somwar
R
R
Konrad
D
D
Garg
R
R
Klip
A
A
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D020928:Mitogen-Activated Protein Kinases; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; C495694:Slc2a4 protein, rat; C494920:Akt1 protein, rat