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A High Fat Diet Impairs Stimulation of Glucose Transport in Muscle

FUNCTIONAL EVALUATION OF POTENTIAL MECHANISMS*
Open AccessPublished:October 02, 1998DOI:https://doi.org/10.1074/jbc.273.40.26157
      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 ∼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-propylamine 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.
      ATB-[2-3H]BMPA
      2-N-4-(1-azi2,2,2-trifluoroethyl)-benzoyl-1,3-bis-(d-mannose-4-yloxy)-2-propylamine
      EDL
      extensor digitorum longus
      BSA
      bovine serum albumin
      3-MG
      3-O-methyl-d-glucose
      MeAIB
      α-(methylamino)isobutyrate
      WGA
      wheat germ agglutinin
      IR
      insulin receptor
      IRS-1
      insulin receptor substrate-1.
      Rodents fed a high fat diet rapidly develop severe whole body and skeletal muscle insulin resistance, hyperinsulinemia, hyperglycemia, and in genetically susceptible strains, diabetes (
      • Kraegen E.W.
      • James D.E.
      • Storlien L.H.
      • Burleigh K.M.
      • Chisholm D.J.
      ,
      • Storlien L.H.
      • James D.E.
      • Burleigh K.M.
      • Chisholm D.J.
      • Kraegen E.W.
      ,
      • Surwit R.S.
      • Kuhn C.M.
      • Cochrane C.
      • McCubbin J.A.
      • Feinglos M.N.
      ,
      • Storlien L.H.
      • Jenkins A.B.
      • Chisholm D.J.
      • Pascoe W.S.
      • Khouri S.
      • Kraegen E.W.
      ,
      • Pagliassotti M.J.
      • Knobel S.M.
      • Shahrokhi K.A.
      • Manzo A.M.
      • Hill J.O.
      ,
      • Han D.H.
      • Hansen P.A.
      • Host H.H.
      • Holloszy J.O.
      ). The high fat diet-fed rodent is of interest as a research model because it might provide insights regarding the mechanisms underlying insulin resistance in obese individuals with impaired glucose tolerance or type 2 diabetes. For example, there is considerable experimental evidence that insulin signaling is impaired in skeletal muscle of obese, insulin-resistant humans (
      • Caro J.F.
      • Sinha M.K.
      • Raju S.M.
      • Ittoop O.
      • Pories W.J.
      • Flickinger E.G.
      • Meelheim D.
      • Dohm G.L.
      ,
      • Arner P.
      • Pollare T.
      • Lithell H.
      • Livingston J.N.
      ,
      • Goodyear L.J.
      • Giorgino F.
      • Sherman L.A.
      • Carey J.
      • Smith R.J.
      • Dohm G.L.
      ), although it is still not clear if the insulin receptor defect is a mechanism involved in the development of the insulin resistance or is a consequence of the insulin resistance. One purpose of this study was to determine whether an insulin-signaling defect is involved in the development of muscle insulin resistance in response to a high fat diet.
      In addition to insulin, glucose transport in skeletal muscle can be stimulated by muscle contractile activity or hypoxia (for review, see Ref.
      • Holloszy J.O.
      • Hansen P.A.
      ). However, 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 (
      • Nesher R.
      • Karl I.E.
      • Kipnis D.M.
      ,
      • Zorzano A.
      • Balon T.W.
      • Goodman M.N.
      • Ruderman N.B.
      ), and the effect of insulin, but not of contractions/hypoxia, is blocked by phosphatidylinositol 3-kinase inhibition (
      • Yeh J.-I.
      • Gulve E.A.
      • Rameh L.
      • Birnbaum M.J.
      ,
      • Lee A.D.
      • Hansen P.A.
      • Holloszy J.O.
      ,
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ). In this context, the finding that stimulation of glucose transport by muscle contractions is also impaired in high fat diet-fed rodents (
      • Han D.H.
      • Hansen P.A.
      • Host H.H.
      • Holloszy J.O.
      ,
      • Rosholt M.N.
      • King P.A.
      • Horton E.S.
      ) suggests the alternative possibility that it is a common step beyond the contraction and insulin-signaling pathways that is involved.
      Stimulation of skeletal muscle glucose transport by either insulin or contractions is mediated by translocation of the GLUT4 isoform of the glucose transporter to the cell surface (
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ,
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ,
      • Wilson C.M.
      • Cushman S.W.
      ). It has been postulated, on the basis of findings of Zierath et al. (
      • Zierath J.R.
      • Houseknecht K.L.
      • Gnudi L.
      • Kahn B.B.
      ), that the insulin resistance induced by fat feeding is mediated by decreased movement of GLUT4 transporters to the cell surface, although this has not been a consistent finding (
      • Rosholt M.N.
      • King P.A.
      • Horton E.S.
      ). The second purpose of this study was to re-evaluate the effect of the high fat diet on insulin-stimulated GLUT4 translocation to the cell surface and to determine whether the diet affects contraction-stimulated GLUT4 translocation.
      The catalytic activity of the glucose transporter proteins is sensitive to changes in the compositional and physical properties of the membrane bilayer (
      • Carruthers A.
      • Melchior D.L.
      ,
      • Sandra A.
      • Fyler D.J.
      • Marshall S.J.
      ), and it has been postulated that the insulin resistance associated with high fat feeding and obesity is mediated, in part, by membrane composition-related reductions in glucose transporter activity (
      • Borkman M.
      • Storlien L.H.
      • Pan D.A.
      • Jenkins A.B.
      • Chisholm D.J.
      • Campbell L.V.
      ,
      • Stevenson R.W.
      • McPherson R.K.
      • Persson L.M.
      • Genereux P.E.
      • Swick A.G.
      • Spitzer J.
      • Herbst J.J.
      • Andrews K.M.
      • Kreutter D.K.
      • Gibbs E.M.
      ). In support of this possibility, Rosholt et al. (
      • Rosholt M.N.
      • King P.A.
      • Horton E.S.
      ) have obtained evidence that a high fat diet results in decreased GLUT4 intrinsic activity in skeletal muscle. The GLUT1 and GLUT4 isoforms of the glucose transporter have a high degree of sequence similarity (
      • James D.E.
      • Strube M.
      • Mueckler M.
      ,
      • Birnbaum M.J.
      ), suggesting that the basic mechanism by which GLUT1 and GLUT4 transport glucose across the plasma membrane is the same. If the hypothesis that a change in plasma membrane composition interferes with GLUT4-mediated glucose transport in muscle of fat-fed rodents is correct, it seems reasonable that glucose transport by the GLUT1 transporter would be similarly affected. Another purpose of the present study was to test the hypothesis that insulin resistance in high fat diet-fed rodents is mediated by an alteration in plasma membrane structure that interferes with glucose transporter function. To this end, we have evaluated the effect of a high fat diet on glucose transport in muscles of mice overexpressing the GLUT1 glucose transporter. We have also examined the effect of the high fat diet on the activity of the system A amino acid transporter, another protein whose function could be affected by compositional changes in the plasma membrane.

      DISCUSSION

      Feeding rodents a high fat diet results in visceral obesity, muscle insulin resistance, and, if continued sufficiently long enough, impaired glucose tolerance or diabetes (
      • Kraegen E.W.
      • James D.E.
      • Storlien L.H.
      • Burleigh K.M.
      • Chisholm D.J.
      ,
      • Storlien L.H.
      • James D.E.
      • Burleigh K.M.
      • Chisholm D.J.
      • Kraegen E.W.
      ,
      • Surwit R.S.
      • Kuhn C.M.
      • Cochrane C.
      • McCubbin J.A.
      • Feinglos M.N.
      ,
      • Storlien L.H.
      • Jenkins A.B.
      • Chisholm D.J.
      • Pascoe W.S.
      • Khouri S.
      • Kraegen E.W.
      ,
      • Pagliassotti M.J.
      • Knobel S.M.
      • Shahrokhi K.A.
      • Manzo A.M.
      • Hill J.O.
      ,
      • Han D.H.
      • Hansen P.A.
      • Host H.H.
      • Holloszy J.O.
      ). One mechanism that has been suggested to explain the insulin resistance of muscle glucose transport that develops with fat feeding and obesity is a change in the lipid composition of the plasma membrane (
      • Storlien L.H.
      • Jenkins A.B.
      • Chisholm D.J.
      • Pascoe W.S.
      • Khouri S.
      • Kraegen E.W.
      ,
      • Borkman M.
      • Storlien L.H.
      • Pan D.A.
      • Jenkins A.B.
      • Chisholm D.J.
      • Campbell L.V.
      ). This seemed a reasonable possibility, as membrane lipid composition can affect the functioning of membrane-associated proteins (reviewed in Ref.
      • Clandinin M.T.
      • Cheema S.
      • Field C.J.
      • Garg M.L.
      • Venkatraman J.
      • Clandinin T.R.
      ), 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. There is considerable evidence that the catalytic activities of the glucose transporters (
      • Carruthers A.
      • Melchior D.L.
      ,
      • Sandra A.
      • Fyler D.J.
      • Marshall S.J.
      ) and the binding properties of the insulin receptor (
      • Gould R.J.
      • Ginsberg B.H.
      • Spector A.A.
      ,
      • van Amelsvoort J.M.M.
      • van der Beek A.
      • Stam J.J.
      ,
      • Field C.J.
      • Ryan E.A.
      • Thomson A.B.R.
      • Clandinin M.T.
      ) are markedly sensitive to changes in the properties of the membrane lipid bilayer.
      Two isoforms of the glucose transporter, GLUT4 (
      • James D.E.
      • Strube M.
      • Mueckler M.
      ,
      • Birnbaum M.J.
      ,
      • Charron M.J.
      • Brosius F.D.
      • Alper S.L.
      • Lodish H.F.
      ,
      • Fukumoto H.
      • Kayano T.
      • Buse J.B.
      • Edwards Y.
      • Pilch P.F.
      • Bell G.I.
      • Seino S.
      ,
      • Kaestner K.H.
      • Christy R.J.
      • McLenithan J.C.
      • Braiterman L.T.
      • Corneliuis P.
      • Pekala P.H.
      • Lane M.D.
      ) and GLUT1 (
      • Birnbaum M.J.
      • Haspel H.C.
      • Rosen O.M.
      ,
      • Mueckler M.
      • Caruso C.
      • Baldwin S.A.
      • Panico M.
      • Blench I.
      • Morris H.R.
      • Allard W.J.
      • Lienhard G.E.
      • Lodish H.F.
      ), are expressed in skeletal muscle. The GLUT4 isoform mediates the increase in glucose transport in response to insulin or muscle contractions by a process that involves the movement of GLUT4 to plasma membrane domains (
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ,
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ,
      • Wilson C.M.
      • Cushman S.W.
      ). The less abundant isoform, GLUT1, seems to reside constitutively in the plasma membrane (
      • Marette E.
      • Richardson J.M.
      • Ramlal T.
      • Balon T.W.
      • Vranic M.
      • Pessin J.E.
      • Klip A.
      ,
      • Wang W.
      • Hansen P.A.
      • Marshall B.A.
      • Holloszy J.O.
      • Mueckler M.
      ) and is thought to mediate basal glucose transport (
      • Marshall B.A.
      • Ren J.-M.
      • Johnson D.W.
      • Gibbs E.M.
      • Lillquist J.S.
      • Soeller W.C.
      • Holloszy J.O.
      • Mueckler M.
      ,
      • Ren J.-M.
      • Marshall B.A.
      • Gulve E.A.
      • Gao J.
      • Johnson D.W.
      • Holloszy J.O.
      • Mueckler M.
      ). These two transporters are structurally similar (
      • James D.E.
      • Strube M.
      • Mueckler M.
      ,
      • Birnbaum M.J.
      ) and are thought to transport glucose across the plasma membrane by the same process. In this context, we used the muscles of transgenic mice that overexpress GLUT1 to evaluate the possibility that a high fat diet causes a change in membrane composition that impairs glucose transporter function. Our results show that a high fat diet that results in severe muscle insulin resistance in wild-type mice has no effect on the high rate of glucose transport in the muscles of GLUT1 overexpressing mice. This finding suggests that an impairment of glucose transporter function mediated by a change in membrane composition is not responsible for the decrease in muscle glucose transport activity caused by a high fat diet. We cannot rule out the possibility that GLUT1 and GLUT4 might respond differently to changes in the composition of the plasma membrane lipid bilayer, but the similarities in the structure of the two transporter isoforms, especially in the putative membrane-spanning regions (
      • James D.E.
      • Strube M.
      • Mueckler M.
      ,
      • Birnbaum M.J.
      ), make this unlikely. Further evidence against a diet-induced change in the composition or physical properties of the plasma membrane that causes a nonspecific decrease in membrane-associated protein activity is provided by our finding that skeletal muscle system A amino acid transport activity is not impaired after 8 weeks on the high fat diet.
      It has been hypothesized on the basis of studies on human skeletal muscle that a defect at the level of the insulin receptor contributes to the insulin resistance associated with obesity (
      • Caro J.F.
      • Sinha M.K.
      • Raju S.M.
      • Ittoop O.
      • Pories W.J.
      • Flickinger E.G.
      • Meelheim D.
      • Dohm G.L.
      ,
      • Arner P.
      • Pollare T.
      • Lithell H.
      • Livingston J.N.
      ,
      • Goodyear L.J.
      • Giorgino F.
      • Sherman L.A.
      • Carey J.
      • Smith R.J.
      • Dohm G.L.
      ). There is much evidence that it is abdominal, particularly visceral, obesity that is associated with insulin resistance (the so called abdominal or central obesity syndrome) (
      • Després J.-P.
      • Nadeau A.
      • Tremblay A.
      • Ferland M.
      • Moorjani S.
      • Lupien P.J.
      • Theriault G.
      • Pinault S.
      • Bouchard C.
      ,
      • Kissebah A.H.
      ). Rodents fed a high fat diet rapidly develop an increase in visceral fat. In rats fed the high fat diet used in the present study, total visceral fat weight (retroperitoneal, mesenteric, and epididymal fat depots) is already ∼50% greater than in chow-fed controls after 8 weeks (
      • Han D.H.
      • Hansen P.A.
      • Host H.H.
      • Holloszy J.O.
      ). In this context, it seemed possible that the insulin resistance induced by a high fat diet could be mediated either by a membrane composition-related change in receptor function (
      • van Amelsvoort J.M.M.
      • van der Beek A.
      • Stam J.J.
      ,
      • Field C.J.
      • Ryan E.A.
      • Thomson A.B.R.
      • Clandinin M.T.
      ,
      • Liu S.
      • Baracos V.E.
      • Quinney H.A.
      • Clandinin M.T.
      ) or as a consequence of decreased receptor number and/or activity associated with the obesity (
      • Caro J.F.
      • Sinha M.K.
      • Raju S.M.
      • Ittoop O.
      • Pories W.J.
      • Flickinger E.G.
      • Meelheim D.
      • Dohm G.L.
      ,
      • Arner P.
      • Pollare T.
      • Lithell H.
      • Livingston J.N.
      ,
      • Goodyear L.J.
      • Giorgino F.
      • Sherman L.A.
      • Carey J.
      • Smith R.J.
      • Dohm G.L.
      ,
      • Le Marchand-Brustel Y.
      • Grémeaux T.
      • Ballotti R.
      • Van Obberghen E.
      ). The initial steps in the stimulation of system A amino acid transport by insulin are the same as those involved in the stimulation of glucose transport (
      • Tsakiridis T.
      • McDowell H.E.
      • Walker T.
      • Downes C.P.
      • Hundal H.S.
      • Vranic M.
      • Klip A.
      ). Our finding that stimulation of MeAIB transport by insulin is not decreased in muscles of rats fed the high fat diet for 8 weeks, therefore, argues against an impairment of insulin receptor function early in the development of the insulin resistance induced by a high fat diet.
      The interpretation that muscle insulin receptor function is normal in rats after 8 weeks on the high fat diet is supported by our finding that stimulated tyrosine kinase activity of solubilized receptors from 8-week fat-fed and chow-fed control rats is similar. Our results are consistent with previous studies in muscle in which relatively short periods of high fat feeding (4–5 weeks) were shown to have little or no effect on insulin binding (
      • Boyd J.J.
      • Contreras I.
      • Kern M.
      • Tapscott E.B.
      • Downes D.L.
      • Frisell W.R.
      • Dohm G.L.
      ,
      • Okamoto M.
      • Okamoto M.
      • Kono S.
      • Inoue G.
      • Hayashi T.
      • Kosaki A.
      • Maeda I.
      • Kubota M.
      • Kuzuya H.
      • Imura H.
      ) and insulin-stimulated autophosphorylation (
      • Okamoto M.
      • Okamoto M.
      • Kono S.
      • Inoue G.
      • Hayashi T.
      • Kosaki A.
      • Maeda I.
      • Kubota M.
      • Kuzuya H.
      • Imura H.
      ) or tyrosine kinase activity (
      • Boyd J.J.
      • Contreras I.
      • Kern M.
      • Tapscott E.B.
      • Downes D.L.
      • Frisell W.R.
      • Dohm G.L.
      ) of partially purified receptors. In addition, the lack of effect of 8 weeks of fat feeding on insulin-stimulated tyrosine phosphorylation of the receptor β-subunit and IRS-1 is in agreement with the findings of Okamotoet al. (
      • Okamoto M.
      • Okamoto M.
      • Kono S.
      • Inoue G.
      • Hayashi T.
      • Kosaki A.
      • Maeda I.
      • Kubota M.
      • Kuzuya H.
      • Imura H.
      ), in which phosphorylation of the insulin receptor and pp190 in rat skeletal muscle following in vivoinsulin administration was not changed by 4 weeks of high fat feeding. However, rats fed the high fat diet for 30 weeks in our studies did have decreases in insulin receptor tyrosine kinase activity and in insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation; by this time, plasma insulin levels in the high fat-fed animals had been elevated for ∼4 months. Thus, our results are consistent with the finding of an insulin receptor defect in muscles of insulin-resistant patients with obesity and glucose intolerance or diabetes (
      • Caro J.F.
      • Sinha M.K.
      • Raju S.M.
      • Ittoop O.
      • Pories W.J.
      • Flickinger E.G.
      • Meelheim D.
      • Dohm G.L.
      ,
      • Arner P.
      • Pollare T.
      • Lithell H.
      • Livingston J.N.
      ,
      • Goodyear L.J.
      • Giorgino F.
      • Sherman L.A.
      • Carey J.
      • Smith R.J.
      • Dohm G.L.
      ), as such individuals have generally been hyperinsulinemic for years. We interpret these findings to indicate that a defect in insulin signaling is a late event that is probably secondary to prolonged hyperinsulinemia and is not a primary cause of the insulin resistance.
      In keeping with the interpretation that the insulin resistance of muscle glucose transport induced by 4–8 weeks on a high fat diet is not due to impairment of insulin signaling is the finding that stimulation of glucose transport by contractile activity, or hypoxia, is also reduced. Contractions and hypoxia stimulate glucose transport by a pathway that is separate from, and independent of, the insulin signaling pathway (
      • Yeh J.-I.
      • Gulve E.A.
      • Rameh L.
      • Birnbaum M.J.
      ,
      • Lee A.D.
      • Hansen P.A.
      • Holloszy J.O.
      ,
      • Lund S.
      • Holman G.D.
      • Schmitz O.
      • Pedersen O.
      ). Since both insulin-stimulated and contraction-stimulated glucose transport are impaired by fat feeding, it seems likely that it is a late, common step that is affected. Our finding that the increases in GLUT4 at the cell surface in response to both insulin and contractions were smaller in muscles of fat-fed rats as compared with controls provides evidence that a step(s) involved in translocation of GLUT4-containing vesicles to, or fusion with, the sarcolemma is impaired. Reduced insulin-stimulated GLUT4 translocation in soleus muscles of mice fed a high fat diet has also been reported by Zierath et al. (
      • Zierath J.R.
      • Houseknecht K.L.
      • Gnudi L.
      • Kahn B.B.
      ). This smaller increase in GLUT4 at the cell surface is not due to a decrease in total muscle GLUT4, as muscle GLUT4 protein content is unaffected in rats fed a high fat diet such as was used in this study (
      • Han D.H.
      • Hansen P.A.
      • Host H.H.
      • Holloszy J.O.
      ,
      • Rosholt M.N.
      • King P.A.
      • Horton E.S.
      ).
      Our finding that the impairment of stimulated transport was greater than the decrease in GLUT4 movement to the cell surface raises the possibility that GLUT4 intrinsic activity may also be reduced in the fat-fed animals. Evidence that a high fat diet may alter GLUT4 intrinsic activity has been provided by Rosholt et al. (
      • Rosholt M.N.
      • King P.A.
      • Horton E.S.
      ), who found that the GLUT4 in plasma membrane vesicles prepared from muscles of high fat diet-fed rats had a lower transport capacity than GLUT4 in vesicles prepared from chow-fed controls. There is currently no information regarding how high fat feeding might bring about a change in intrinsic activity. One possibility is that the GLUT4 protein is modified prior to translocation. Another possibility is that the composition of the GLUT4 vesicle-derived lipid annulus of the transporter protein is changed. The third possibility, that reduced intrinsic activity of GLUT4 could be mediated by changes in the membrane lipid composition that result in impaired function of the transporter after its insertion into the plasma membrane, now seems unlikely in light of our finding that activity of the GLUT1 transporter, which is constitutively targeted to the plasma membrane, is unaffected.
      In conclusion, our findings on muscles of transgenic mice overexpressing the GLUT1 glucose transporter provide evidence that the impairment of muscle glucose transport induced by a high fat diet is not due to a change in sarcolemmal composition that interferes with glucose transporter function. Our results further show that insulin receptor down-regulation does not play a primary role in causing the muscle insulin resistance induced by feeding a high fat diet. Both the contraction-stimulated and insulin-stimulated increases in GLUT4 at the cell surface are reduced in muscles of fat-fed rats, suggesting an impairment of one or more of the steps involved in the GLUT4 translocation process.

      ACKNOWLEDGEMENTS

      We thank Tim Meyer, Vanessa Kieu, and Nancy Ensor for excellent technical assistance.

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