title: High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect.
abstract: Glucose transport in skeletal muscle can be mediated by two separate pathways, one stimulated by insulin and the other by muscle contraction. High-fat feeding impairs glucose transport in muscle, but the mechanism remains unclear. FVB mice (3 weeks old) were fed a high-fat diet (55% fat, 24% carbohydrate, 21% protein) or standard chow for 3-4 weeks or 8 weeks. Insulin-stimulated glucose transport, assessed with either 2-deoxyglucose or 3-O-methylglucose was decreased 35-45% (P < 0.001) in isolated soleus muscle, regardless of diet duration. Similarly, glucose transport stimulated by okadaic acid, a serine/threonine phosphatase inhibitor, was also 45% lower with high-fat feeding, but the glucose transport response to hypoxia or N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) (which are stimulators of the "contraction pathway") was intact. Hexokinase I, II, and total activity were normal in soleus muscle from high-fat-fed mice. GLUT4 expression in soleus muscle from the high-fat-fed mice was also normal, but the insulin-stimulated cell surface recruitment of GLUT4 assessed by exofacial photolabeling with [3H]-ATB bis-mannose was reduced by 50% (P < 0.001). Insulin-receptor substrate 1 (IRS-1) associated phosphatidylinositol (PI) 3-kinase activity stimulated by insulin was also reduced by 36% (P < 0.001), and expression of p85 and p110b subunits of PI 3-kinase was normal. In conclusion, high-fat feeding selectively impairs insulin-stimulated, but not contraction-pathway-mediated, glucose transport by reducing GLUT4 translocation to the plasma membrane. This appears to result from an acquired defect in insulin activation of PI 3-kinase. Since effects of okadaic acid on glucose transport are independent of PI 3-kinase, a second signaling defect may also be induced.
authors.affiliation: Department of Medicine at Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts, USA. jrz@klinfys.ks.se
authors.forename: J R
authors.initials: JR
authors.lastname: Zierath
authors.forename: K L
authors.initials: KL
authors.lastname: Houseknecht
authors.forename: L
authors.initials: L
authors.lastname: Gnudi
authors.forename: B B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D002451:Cell Compartmentation; D004041:Dietary Fats / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051275:Glucose Transporter Type 4; D006593:Hexokinase / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D013449:Sulfonamides; D019319:Okadaic Acid; C017967:W 7; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D006593:Hexokinase; D011493:Protein Kinase C