Abstract
A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feeding causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors. Epitrochlearis muscles of rats fed a high (50% of calories) fat diet for 8 weeks showed approximately 50% decreases in insulin- and contraction-stimulated 3-O-methylglucose transport. Similar decreases in stimulated glucose transport activity occurred in muscles of wild-type mice with 4 weeks of fat feeding. In contrast, GLUT1 overexpressing muscles of transgenic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose transporter function. Insulin-stimulated system A amino acid transport, insulin receptor (IR) tyrosine kinase activity, and insulin-stimulated IR and IRS-1 tyrosine phosphorylation were all normal in muscles of rats fed the high fat diet for 8 weeks. However, after 30 weeks on the high fat diet, there was a significant reduction in insulin-stimulated tyrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the 3H-labeled 2-N-4-(1-azi-2,2, 2-trifluoroethyl)-benzoyl-1,3-bis-(D-mannose-4-yloxy)-2-propyla min e photolabel, were 26-36% smaller in muscles of the 8-week high fat-fed rats as compared with control rats. Our findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane composition-related reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.
Highlights
A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions
Our findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane compositionrelated reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport
This seemed a reasonable possibility, as membrane lipid composition can affect the functioning of membrane-associated proteins, and two of the key proteins involved in the regulation of glucose transport, the glucose transporter and the insulin receptor, are constituents of the plasma membrane
Summary
A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. The signaling pathways by which insulin and contractions/hypoxia stimulate glucose transport are distinct, as evidenced by the findings that their maximal effects on glucose transport are additive [11, 12], and the effect of insulin, but not of contractions/hypoxia, is blocked by phosphatidylinositol 3-kinase inhibition [13,14,15] In this context, the finding that stimulation of glucose transport by muscle contractions is impaired in high fat diet-fed rodents [6, 16] suggests the alternative possibility that it is a common step beyond the contraction and insulin-signaling pathways that is involved
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