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Fat Feeding and Muscle Fat Deposition Eliciting Insulin Resistance

An Update

  • Chapter
The Metabolic Syndrome

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Skeletal muscle insulin resistance, defined as a reduced ability of insulin to stimulate tissue utilization and storage of glucose, is an early and major perturbation in the metabolic syndrome. Clinical conditions under the umbrella of the metabolic syndrome include obesity, type 2 diabetes, dyslipidemia, and hypertension, and are known to be influenced by lifestyle factors such as diet and activity. The metabolic syndrome is reaching alarming proportions in many societies. This chapter considers the increasingly compelling evidence that links insulin resistance with the situation when fatty acid supply exceeds energy demand in muscle, resulting in an accumulation of lipid in this tissue. This chapter is an update of a similar-titled chapter written some five years ago (1), and we highlight how knowledge has progressed since 2000. Considered are evidence for the association between fatty acid metabolism and muscle insulin resistance, possible causal links whereby increased muscle lipid accumulation could result in impaired insulin signalling and insulin resistance, and therapeutic options for ameliorating insulin resistance based on a “lipid-lowering” approach. We also consider how a scenario of excess fatty acid supply to muscle stands in relation to other emerging theories of factors contributing to muscle insulin resistance in obesity and similar states.

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References

  1. Kraegen EW, Cooney GJ, Ye JM, Furler SM. Fat feeding and muscle fat deposition eliciting insulin resistance. In: Insulin Resistance and Insulin Resistance Syndrome, Hansen B, Shafrir E (eds.), Taylor & Francis, London, 2002, pp. 195–209.

    Google Scholar 

  2. Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence of dietary fat composition on development of insulin resistance in rats. Diabetes 1991; 40:280–289.

    CAS  PubMed  Google Scholar 

  3. Kraegen EW, Clark PW, Jenkins AB, Daley EA, Chisholm DJ, Storlien LH. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 1991; 40:1397–1403.

    CAS  PubMed  Google Scholar 

  4. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350:664–671.

    CAS  PubMed  Google Scholar 

  5. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51:2944–2950.

    CAS  PubMed  Google Scholar 

  6. Hwang JH, Pan JW, Heydari S, Hetherington HP, Stein DT. Regional differences in intramyocellular lipids in humans observed by in vivo H-1-MR spectroscopic imaging. J Appl Physiol 2001; 90:1267–1274.

    CAS  PubMed  Google Scholar 

  7. Kraegen EW, James DE, Storlien LH, Burleigh KM, Chisholm DJ. In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: Assessment by euglycaemic clamp plus deoxyglucose administration. Diabetologia 1986; 29:192–198.

    CAS  PubMed  Google Scholar 

  8. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle: Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; i:785–789.

    Google Scholar 

  9. Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 1999; 39:E1–E18.

    Google Scholar 

  10. Oakes ND, Bell KS, Furler SM, Camilleri S, Saba AK, Ruderman NB, Chisholm DJ, Kraegen EW. Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: Parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA. Diabetes 1997; 46:2022–2028.

    CAS  PubMed  Google Scholar 

  11. Prentki M, Corkey BE. Are the beta-cell signalling molecules malonyl-CoA and cytosolic longchain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 1996; 45:273–283.

    CAS  PubMed  Google Scholar 

  12. Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. Cell Signal 2000; 12:583–594.

    CAS  PubMed  Google Scholar 

  13. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 2006; 45:42–72.

    CAS  PubMed  Google Scholar 

  14. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112:1796–1808.

    CAS  PubMed  Google Scholar 

  15. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112:1821–1830.

    CAS  PubMed  Google Scholar 

  16. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: A key component of the obesitydiabetes link. Diabetes 1994; 43:1271–1278.

    CAS  PubMed  Google Scholar 

  17. Shimabukuro M, Koyama K, Chen GX, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Nat Acad Sci 1997; 94:4637–4641.

    CAS  PubMed  Google Scholar 

  18. Fernandez-Real JM, Broch M, Vendrell J, Gutierrez C, Casamitjana R, Pugeat M, Richart C, Ricart W. Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 2000; 49:517–520.

    CAS  PubMed  Google Scholar 

  19. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409:307–312.

    CAS  PubMed  Google Scholar 

  20. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005; 26:439–451.

    CAS  PubMed  Google Scholar 

  21. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science 2005; 307:426–430.

    CAS  PubMed  Google Scholar 

  22. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005; 436:356–362.

    CAS  PubMed  Google Scholar 

  23. Thompson AL, Lim-Fraser MY-C, Kraegen EW, Cooney GJ. Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro. Am J Physiol 2000; 279: E577–E584.

    CAS  Google Scholar 

  24. Sinha S, Perdomo G, Brown NF, O’Doherty RM. Fatty acid-induced insulin resistance in L6 myotubes is prevented by inhibition of activation and nuclear localization of nuclear factor kappa B. J Biol Chem 2004; 279:41294–41301.

    CAS  PubMed  Google Scholar 

  25. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46:3–10.

    CAS  PubMed  Google Scholar 

  26. Chalkley S, Hettiarachchi M, Chisholm DJ, Kraegen EW. Five hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat. Metabolism 1998; 47:1121–1126.

    CAS  PubMed  Google Scholar 

  27. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48:1270–1274.

    CAS  PubMed  Google Scholar 

  28. Yu C, Chen Y, Zong H, Wang Y, Bergeron R, Kim JK, Cline GW, Cushman SW, Cooney GJ, Atcheson B, White MW, Kraegen EW, Shulman GI. Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277:50230–50236.

    CAS  PubMed  Google Scholar 

  29. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA, Cusi K. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005; 54:1640–1648.

    CAS  PubMed  Google Scholar 

  30. Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C. Effects of fat on insulin stimulated carbohydrate metabolism in normal men. J Clin Invest 1991; 88:960–966.

    CAS  PubMed  Google Scholar 

  31. Boden G, Chen XH, Ruiz J, White JV, Rossetti L. Mechanisms of fatty acid induced inhibition of glucose uptake. J Clin Invest 1994; 93:2438–2446.

    CAS  PubMed  Google Scholar 

  32. Kelley DE, Mokan M, Simoneau JA, Mandarino LJ. Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 1993; 92:91–98.

    CAS  PubMed  Google Scholar 

  33. Kim JK, Youn JH. Prolonged suppression of glucose metabolism causes insulin resistance in rat skeletal muscle. Am J Physiol 1997; 272:E288–E296.

    CAS  PubMed  Google Scholar 

  34. Jucker BM, Rennings AJM, Cline GW, Shulman GI. C-13 and P-31 NMR studies on the effects of increased plasma free fatty acids on intramuscular glucose metabolism in the awake rat. J Biol Chem 1997; 272:10464–10473.

    CAS  PubMed  Google Scholar 

  35. Bevilacqua S, Buzzigoli G, Bonadonna R, Brandi LS, Oleggini M, Boni C, Geloni M, Ferrannini E. Operation of Randle’s cycle in patients with NIDDM. Diabetes 1990; 39:383–389.

    CAS  PubMed  Google Scholar 

  36. Wolfe BM, Klein S, Peters EJ, Schmidt BF, Wolfe RR. Effect of elevated free fatty acids on glucose oxidation in normal humans. Metabolism 1988; 37:323–329.

    CAS  PubMed  Google Scholar 

  37. Jenkins AB, Storlien LH, Chisholm DJ, Kraegen EW. Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo. J Clin Invest 1988; 82:293–299.

    CAS  PubMed  Google Scholar 

  38. Chen MT, Kaufman LN, Spennetta T, Shrago E. Effects of high fat-feeding to rats on the interrelationship of body weight, plasma insulin, and fatty acyl-coenzyme-A esters in liver and skeletal muscle. Metabolism 1992; 41:564–569.

    CAS  PubMed  Google Scholar 

  39. Zierath JB, Houseknecht KL, Gnudi L, Kahn BB. High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. Diabetes 1997; 46:215–223.

    CAS  PubMed  Google Scholar 

  40. Frangioudakis G, Ye JM, Cooney GJ. Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation. Endocrinology 2005; 146:5596–5603.

    CAS  PubMed  Google Scholar 

  41. Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 2001; 50:123–130.

    CAS  PubMed  Google Scholar 

  42. Kim JK, Fillmore JJ, Chen Y, Yu CL, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 2001; 98:7522–7527.

    CAS  PubMed  Google Scholar 

  43. Ferreira L, Pulawa LK, Jensen DR, Eckel RH. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes 2001; 50: 1064–1068.

    CAS  PubMed  Google Scholar 

  44. Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GJ. Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest 2004; 113:756–763.

    CAS  PubMed  Google Scholar 

  45. Ibrahimi A, Bonen A, Blinn WD, Hajri T, Li X, Zhong K, Cameron R, Abumrad NA. Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin. J Biol Chem 1999; 274:26761–26766.

    CAS  PubMed  Google Scholar 

  46. Campbell SE, Tandon NN, Woldegiorgis G, Luiken JJ, Glatz JF, Bonen A. A novel function for fatty acid translocase (FAT)/CD36: involvement in long chain fatty acid transfer into the mitochondria. J Biol Chem 2004; 279: 36235–36241.

    CAS  PubMed  Google Scholar 

  47. Park SY, Kim HJ, Wang S, Higashimori T, Dong J, Kim YJ, Cline G, Li H, Prentki M, Shulman GI, Mitchell GA, Kim JK. Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. Am J Physiol Endocrinol Metab 2005; 289:E3D–39.

    Google Scholar 

  48. Goudriaan JR, Tacken PJ, Dahlmans VE, Gijbels MJ, van Dijk KW, Havekes LM, Jong MC. Protection from obesity in mice lacking the VLDL receptor. Arterioscler Thromb Vasc Biol 2001; 21:1488–1493.

    CAS  PubMed  Google Scholar 

  49. Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987; 237:885–888.

    CAS  PubMed  Google Scholar 

  50. Neschen S, Moore I, Regittnig W, Yu CL, Wang YL, Pypaert M, Petersen KF, Shulman GI. Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content. Amer J Physiol 2002; 282:E395–E401.

    CAS  Google Scholar 

  51. Russell JC, Shillabeer G, Bartana J, Lau DCW, Richardson M, Wenzel LM, Graham SE, Dolphin PJ. Development of insulin resistance in the jcr-La-Cp rat: Role of triacylglycerols and effects of Medica 16. Diabetes 1998; 47:770–778.

    CAS  PubMed  Google Scholar 

  52. Prada PO, Zecchin HG, Gasparetti AL, Torsoni MA, Deno M, Hirata AE, Corezola do Amaral ME, Hoer NF, Boschero AC, Saad MJ. Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1 ser307 phosphorylation in a tissue-specific fashion. Endocrinology 2005; 146:1576–1587.

    CAS  PubMed  Google Scholar 

  53. Oakes ND, Camilleri S, Furler SM, Chisholm DJ, Kraegen EW. The insulin sensitizer, BRL 49653, reduces systemic fatty acid supply and utilization and tissue lipid availability in the rat. Metabolism 1997; 46:935–942.

    CAS  PubMed  Google Scholar 

  54. Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW. Peroxisome proliferatoractivated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: Comparison with PPAR-gamma activation. Diabetes 2001; 50:411–417.

    CAS  PubMed  Google Scholar 

  55. Kim SP, Ellmerer M, Van Citters GW, Bergman RN. Primacy of hepatic insulin resistance in the development of the metabolic syndrome induced by an isocaloric moderate-fat diet in the dog. Diabetes 2003; 52:2453–2460.

    CAS  PubMed  Google Scholar 

  56. Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997; 46:983–988.

    CAS  PubMed  Google Scholar 

  57. Phillips DIW, Caddy S, Hic V, Fielding BA, Frayn KN, Borthwick AC, Taylor R. Intramuscular triglyceride and muscle insulin sensitivity: Evidence for a relationship in nondiabetic subjects. Metabolism 1996; 45:947–950.

    CAS  PubMed  Google Scholar 

  58. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: Evidence for a paradox in endurance-trained athletes. J Clin Endoc Metab 2001; 86:5755–5761.

    CAS  Google Scholar 

  59. Goodpaster BH, Theriault R, Watkins SC, Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism 2000; 49:467–472.

    CAS  PubMed  Google Scholar 

  60. Boesch C, Slotboom J, Hoppeler H, Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized H-1-MR-spectroscopy. Magn Reson Med 1997; 37:484–493.

    CAS  PubMed  Google Scholar 

  61. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT. Measurement of intracellular triglyceride stores by H spectroscopy: Validation in vivo. Am J Physiol 1999; 276:E977–E989.

    CAS  PubMed  Google Scholar 

  62. Levin K, Schroeder HD, Alford FP, Beck-Nielsen H. Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes. Diabetologia 2001; 44:824–833.

    CAS  PubMed  Google Scholar 

  63. Krssak M, Petersen KF, Dresner A, DiPietro L, Vogel SM, Rothman DL, Shulman GI, Roden M. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: An H-1 NMR spectroscopy study. Diabetologia 1999; 42:113–116.

    CAS  PubMed  Google Scholar 

  64. Jacob S, Machann J, Rett K, Brechtel K, Yolk A, Renn A, Maerker E, Matthaei S, Schick F, Claussen C-D, Haring H-U. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of Type 2 diabetic subjects. Diabetes 1999; 48:1113–1119.

    CAS  PubMed  Google Scholar 

  65. Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzatic A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: An H-1-C-13 nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 1999; 48:1600–1606.

    CAS  PubMed  Google Scholar 

  66. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen AM, Yki-Jarvinen H. Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 2001; 50:2337–2343.

    CAS  PubMed  Google Scholar 

  67. Kriketos AD, Furler SM, Gan SK, Poynten AM, Chisholm OJ, Campbell LV. Multiple indexes of lipid availability are independently related to whole body insulin action in healthy humans. J Clin Endocrinol Metab 2003; 88:793–798.

    CAS  PubMed  Google Scholar 

  68. Gan SK, Samaras K, Thompson CH, Kraegen EW, Carr A, Cooper DA, Chisholm DJ. Altered myocellular and abdominal fat partitioning predict disturbance in insulin action in HIV protease inhibitor-related lipodystrophy. 2002; Diabetes 51: 3163–3169.

    Google Scholar 

  69. Gavrilova 0, Marcus-Samuels B, Graham 0, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105:271–278.

    CAS  PubMed  Google Scholar 

  70. Gan SK, Kriketos AD, Poynten AM, Furler SM, Thompson CH, Kraegen EW, Campbell LV, Chisholm DJ. Insulin action, regional fat, and myocyte lipid: altered relationships with increased adiposity. Obes Res 2003; 11:1295–1305.

    CAS  PubMed  Google Scholar 

  71. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: A reexamination. Diabetes 2000; 49:677–683.

    CAS  PubMed  Google Scholar 

  72. Kiens B. Skeletal muscle lipid metabolism in exercise and insulin resistance. Physiol Rev 2006; 86:205–243.

    CAS  PubMed  Google Scholar 

  73. Bruce CR, Kriketos AD, Cooney GJ, Hawley JA. Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with Type 2 diabetes. Diabetologia 2004; 47:23–30.

    CAS  PubMed  Google Scholar 

  74. Vock R, Weibel ER, Hoppeler H, Ordway G, Weber JM, Taylor CR. Design of the oxygen and substrate pathways: V. Structural basis of vascular substrate supply to muscle cells. J Exp Biol 1996; 199:1675–1688.

    CAS  PubMed  Google Scholar 

  75. Bruce CR, Anderson MJ, Carey AL, Newman DG, Bonen A, Kriketos AD, Cooney GJ, Hawley JA. Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status. J Clin Endocrinol Metab 2003; 88:5444–5451.

    CAS  PubMed  Google Scholar 

  76. Bruce CR, Thrush AB, Mertz VA, Bezaire V, Chabowski A, Heigenhauser GJ, Dyck DJ. Endurance training in obese humans improves glucose tolerance, mitochondrial fatty acid oxidation and alters muscle lipid content. Am J Physiol Endocrinol Metab 2006; in press.

    Google Scholar 

  77. Faergeman NJ, Knudsen J. Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and cell signalling. Biochem J 1997; 323:1–12.

    CAS  PubMed  Google Scholar 

  78. Carroll JE, Villadiego A, Morse DP. Fatty acid oxidation intermediates and the effect of fasting on oxidation in red and white skeletal muscle. Muscle & Nerve 1983; 6:367–373.

    CAS  Google Scholar 

  79. Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997; 46:1768–1774.

    CAS  PubMed  Google Scholar 

  80. Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, Cooney GJ. Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol 2000; 279:E554–E560.

    CAS  Google Scholar 

  81. Kim JK, Kim HJ, Park SY, Cederberg A, Westergren R, Nilsson D, Higashimori T, Cho YR, Liu ZX, Dong J, Cline GW, Enerback S, Shulman GI. Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Diabetes 2005; 54:1657–1663.

    CAS  PubMed  Google Scholar 

  82. Bajaj M, Suraamornkul S, Romanelli A, Cline GW, Mandarino LJ, Shulman GI, DeFronzo RA. Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients. Diabetes 2005; 54:3148–3153.

    CAS  PubMed  Google Scholar 

  83. Houmard JA, Tanner CJ, Yu CL, Cunningham PG, Pories WJ, MacDonald KG, Shulman GI. Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty Acyl-CoAs in morbidly obese subjects. Diabetes 2002; 51:2959–2963.

    CAS  PubMed  Google Scholar 

  84. Vessby B, Gustafsson IB, Tengblad S, Boberg M, Andersson A. Desaturation and elongation of Fatty acids and insulin action. Ann NY Acad Sci 2002; 967:183–195.

    CAS  PubMed  Google Scholar 

  85. Voss MD, Beha A, Tennagels N, Tschank G, Herling AW, Quint M, Ged M, Metz-Weidmann C, Haun G, Kom M. Gene expression profiling in skeletal muscle of Zucker diabetic fatty rats: Implications for a role of stearoyl-CoA desaturase 1 in insulin resistance. Diabetologia 2005; 48:2622–2630.

    CAS  PubMed  Google Scholar 

  86. Wititsuwannakul D, Kim K-H. Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. J Biol Chem 1977; 252:7812–7817.

    CAS  PubMed  Google Scholar 

  87. Tippett PS, Neet KE. An allosteric model for the inhibition of glucokinase by long acyl coenzyme A. J Biol Chem 1982; 257:12846–12852.

    CAS  PubMed  Google Scholar 

  88. Fulceri R, Gamberucci A, Scott HM, Giunti R, Burchell A, Benedetti A. Fatty acyl-CoA esters inhibit glucose-6-phosphatase in rat liver microsomes. Biochem J 1995; 307:391–397.

    CAS  PubMed  Google Scholar 

  89. Nikawa J-I, Tanabe T, Ogiwara H, Shiba T, Numa S. Inhibitory effects of long-chain acyl coenzyme A analogues on liver acetyl coenzyme A carboxylase. FEBS Lett 1979; 102:223–226.

    CAS  PubMed  Google Scholar 

  90. Thompson AL, Cooney GJ. Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes 2000; 49:1761–1765.

    CAS  PubMed  Google Scholar 

  91. Taylor EB, Ellingson WJ, Lamb JD, Chesser DG, Winder WW. Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25. Am J Physiol 2005; 288:E1055–1061.

    CAS  Google Scholar 

  92. Ruderman NB, Saba AK, Kraegen EW. Minireview: Malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 2003; 144:5166–5171.

    CAS  PubMed  Google Scholar 

  93. Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 1997; 46:169–178.

    CAS  PubMed  Google Scholar 

  94. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O’Brien WR, Littman DR, Shulman GI. PKC-theta knockout mice are protected from fatinduced insulin resistance. J Clin Invest 2004; 114:823–827.

    CAS  PubMed  Google Scholar 

  95. Laybutt DR, Schmitz-Peiffer C, Saha AK, Ruderman NB, Biden TJ, Kraegen EW. Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat. Am J Physioll 1999; 277:EI07Q–EI076.

    Google Scholar 

  96. Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999; 274:24202–24210.

    CAS  PubMed  Google Scholar 

  97. Adams JM II, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards Me, Mandarino LJ. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53:25–31.

    CAS  PubMed  Google Scholar 

  98. Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M, Zendzian-Piotrowska M, Brzezinska Z, Gorski J. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 2004; 53:1215–1221.

    CAS  PubMed  Google Scholar 

  99. Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am J Physiol 2006; 290:E471–479.

    CAS  Google Scholar 

  100. Jump DB. Fatty acid regulation of gene transcription. Crit Rev Clin Lab Sci 2004; 41:41–78.

    CAS  PubMed  Google Scholar 

  101. Duplus E, Glorian M, Forest C. Fatty acid regulation of gene transcription. J Biol Chem 2000; 275:30749–30752.

    CAS  PubMed  Google Scholar 

  102. Lemberger T, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: A nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996; 12:335–363.

    CAS  PubMed  Google Scholar 

  103. Spiegelman BM. PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47:507–514.

    CAS  PubMed  Google Scholar 

  104. Fabris R, Nisoli E, Lombardi AM, Tonello C, Serra R, Granzotto M, Cusin I, Bohner-Jeanrenaud F, Federspil G, Carruba MO, Vettor R. Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats. Diabetes 2001; 50:601–608.

    CAS  PubMed  Google Scholar 

  105. Hegarty BD, Cooney GJ, Kraegen EW, Furler SM. Increased efficiency of fatty acid uptake contributes to lipid accumulation in skeletal muscle of high fat-fed insulin-resistant rats. Diabetes 2002; 51:1477–1484.

    CAS  PubMed  Google Scholar 

  106. Bonen A, Parolin ML, Steinberg GR, Calles-Escandon J, Tandon NN, Glatz JF, Luiken JJ, Heigenhauser GJ, Dyck DJ. Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. Faseb J 2004; 18:1144–1146.

    CAS  PubMed  Google Scholar 

  107. de Fourmestraux V, Neubauer H, Poussin C, Farmer P, Falquet L, Burcelin R, Delorenzi M, Thorens B. Transcript profiling suggests that differential metabolic adaptation of mice to a high fat diet is associated with changes in liver to muscle lipid fluxes. J Biol Chern 2004; 279:50743–50753.

    Google Scholar 

  108. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005; 54:1926–1933.

    CAS  PubMed  Google Scholar 

  109. Sreekumar R, Unnikrishnan J, Fu A, Nygren J, Short KR, Schimke J, Barazzoni R, Nair KS. Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle. Am J Physiol 2002; 282:E1055–1061.

    CAS  Google Scholar 

  110. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 2005; 280:10290–10297.

    CAS  PubMed  Google Scholar 

  111. Pan DA, Hulbert AJ, Storlien LH. Dietary fats, membrane phospholipids and obesity. J Nutr 1994; 124:1555–1565.

    CAS  PubMed  Google Scholar 

  112. Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty acid composition of skeletal-muscle phospholipids. N Engl J Med 1993; 328:238–244.

    CAS  PubMed  Google Scholar 

  113. Haugaard SB, Madsbad S, Hoy CE, Vaag A. Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects: Implications for insulin sensitivity. Clin Endocrinol (Oxf) 2006; 64:169–78.

    CAS  Google Scholar 

  114. Storlien LH, Kriketos AD, Calvert GD, Baur LA, Jenkins AB. Fatty acids, triglycerides and syndromes of insulin resistance. Prostagland Leuk Essent Fatty Acids 1997; 57:379–385.

    CAS  Google Scholar 

  115. Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, Calvert GD, Campbell LV. Dietary fats and insulin action. Diabetologia 1996; 39:621–631.

    CAS  PubMed  Google Scholar 

  116. Malenfant P, Tremblay A, Doucet E, Imbeault P, Simoneau JA, Joanisse DR. Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training. Am J Physiol 2001; 280:E632–E639.

    CAS  Google Scholar 

  117. Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996; 45:633–638.

    CAS  PubMed  Google Scholar 

  118. Park KS, Rhee BD, Lee K-U, Kim SY, Lee HK, Koh C-S, Min HK. Intra-abdominal fat is associated with decreased insulin sensitivity in healthy young men. Metabolism 1991; 40:600–603.

    CAS  PubMed  Google Scholar 

  119. Ross R, Fortier L, Hudson R. Separate associations between visceral and subcutaneous adipose tissue distribution, insulin and glucose levels in obese women. Diabetes Care 1996; 19:1404–1411.

    CAS  PubMed  Google Scholar 

  120. Simoneau J-A, Colberg SR, Thaete FL, Kelley DE. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J 1995; 9:273–278.

    CAS  PubMed  Google Scholar 

  121. Gan SK, Samaras K, Thompson C, Kraegen EW, Carr A, Cooper D, Chisholm DJ. Correlations between intramyocellular lipid, visceral fat and insulin sensitivity: A study of HIV positive subjects with and without peripheral lipodystrophy. Diabetes 2001; 50(suppl 2):A315–316.

    Google Scholar 

  122. Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, Boselli L, Barbetta G, Allen K, Rife F, Savoye M, Dziura J, Sherwin R, Shulman GI, Caprio S. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 2003; 362:951–957.

    CAS  PubMed  Google Scholar 

  123. Carey DGP, Campbell LV, Chisholm DJ. Is visceral fat (intra-abdominal and hepatic) a major determinant of gender differences in insulin resistance and dyslipidemia? Diabetes 1996; 45(suppl): 110A.

    Google Scholar 

  124. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD._Splanchnic lipolysis in human obesity. J Clin Invest 2004; 113:1582–1588.

    CAS  PubMed  Google Scholar 

  125. Barzilai N, She L, Liu BQ, Vuguin P, Cohen P, Wang JL, Rossetti L. Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 1999; 48:94–98.

    CAS  PubMed  Google Scholar 

  126. Einstein PH, Atzmon G, Yang XM, Ma XH, Rincon M, Rudin E, Muzumdar R, Barzilai N. Differential responses of visceral and subcutaneous fat depots to nutrients. Diabetes 2005; 54:672–678.

    CAS  PubMed  Google Scholar 

  127. Lebovitz HE, Banerji MA. Point: visceral adiposity is causally related to insulin resistance. Diabetes Care 2005; 28:2322–2325.

    PubMed  Google Scholar 

  128. Miles JM, Jensen MD. Counterpoint: Visceral adiposity is not causally related to insulin resistance. Diabetes Care 2005; 28:2326–2328.

    PubMed  Google Scholar 

  129. Sidossis LS, Stuart CA, Shulman GI, Lopaschuk GD, Wolfe RR. Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria. J Clin Invest 1996; 98:2244–2250.

    CAS  PubMed  Google Scholar 

  130. Wolfe RR. Metabolic interactions between glucose and fatty acids in humans. Amer J Clin Nutr 1998; 67:S519–S526.

    Google Scholar 

  131. Ruderman N, Prentki M. AMP kinase and malonyl-CoA: Targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3:340–351.

    CAS  PubMed  Google Scholar 

  132. Laybutt DR, Chisholm DJ, Kraegen EW. Specific adaptations in muscle and adipose tissue in response to chronic systemic glucose oversupply in rats. Am._J Physiol 1997; 36:E1–E9.

    Google Scholar 

  133. Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA. Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 279:E1039–1044.

    CAS  PubMed  Google Scholar 

  134. Hegarty BD, Furler SM, Oakes ND, Kraegen EW, Cooney GJ. Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo: A study using the novel PPARalphalgamma agonist tesaglitazar. Endocrinology 2004; 145:3158–3164.

    CAS  PubMed  Google Scholar 

  135. Cameron-Smith D, Burke LM, Angus DJ, Tunstall RJ, Cox GR, Bonen A, Hawley JA, Hargreaves M. A short-term, high-fat diet up-regulates lipid metabolism and gene expression in human skeletal muscle. Am J Clin Nutr 2003; 77:313–318.

    CAS  PubMed  Google Scholar 

  136. Evans K, Clark ML, Frayn KN. Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism. Am J Physiol 1999; 276:E241–248.

    CAS  PubMed  Google Scholar 

  137. Frayn KN. Non-esterified fatty acid metabolism and postprandial lipaemia. Atherosclerosis 1998; 141(suppl 1):S41–416.

    Google Scholar 

  138. Purler SM, Wilks DL, Preston E, Frangioudakis G, Cooney GJ, Kraegen EW. A diet high in saturated fat blunts the tissue-specific adaptation of lipoprotein lipase activity to feeding in rats. Diabetologia 2005; 48:A237–A237.

    Google Scholar 

  139. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001; 108:437–446.

    CAS  PubMed  Google Scholar 

  140. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesityand diet-induced insulin resistance with salicylates or targeted disruption of Ikkß. Science 2001; 293:1673–1677.

    CAS  PubMed  Google Scholar 

  141. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C and IkB-alpha. Diabetes 2002; 51:2005–2011.

    CAS  PubMed  Google Scholar 

  142. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 2002; 109:1321–1326.

    CAS  PubMed  Google Scholar 

  143. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420:333–336.

    CAS  PubMed  Google Scholar 

  144. Hotamisligil GS. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes 2005; 54(suppl 2):S73–78.

    CAS  PubMed  Google Scholar 

  145. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005; 1:15–25.

    CAS  PubMed  Google Scholar 

  146. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005; 54:2460–2470.

    CAS  PubMed  Google Scholar 

  147. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell 2005; 123:993–999.

    CAS  PubMed  Google Scholar 

  148. Lehmann JM, Moore LB, Smitholiver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma). J Biol Chem 1995; 270:12953–12956.

    CAS  PubMed  Google Scholar 

  149. Oakes ND, Kennedy CJ, Jenkins AB, Laybutt DR, Chisholm DJ, Kraegen EW. A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat. Diabetes 1994; 43:1203–1210.

    CAS  PubMed  Google Scholar 

  150. Oakes ND, Thalen PG, Jacinto SM, Ljung B. Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability. Diabetes 2001; 50:1158–1165.

    CAS  PubMed  Google Scholar 

  151. Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: Comparison with metformin. Diabetologia 2004; 47:1306–1313.

    CAS  PubMed  Google Scholar 

  152. Schmitz-Peiffer C, Oakes ND, Browne CL, Kraegen EW, Biden TJ. Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653. Am J Physiol 1997; 273: E915–E921.

    CAS  PubMed  Google Scholar 

  153. Bahr M, Spelleken M, Bock M, Vonholtey M, Kiehn R, Eckel J. Acute and chronic effects of Troglitazone (CS-045) on isolated rat ventricular cardiomyocytes. Diabetologia 1996; 39:766–774.

    CAS  PubMed  Google Scholar 

  154. Park KS, Ciaraldi TP, Abramscarter L, Mudaliar S, Nikoulina SE, Henry RR. Troglitazone regulation of glucose metabolism in human skeletal muscle cultures from obese Type II diabetic subjects. J Clin EndocrinolMetab 1998; 83:1636–1643.

    CAS  Google Scholar 

  155. Kintscher U, Law RE. PPARgamma-mediated insulin sensitization: The importance of fat versus muscle. Am J Physiol 2005; 288:E287–291.

    CAS  Google Scholar 

  156. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky JM, Evans RM. Adipose-specific peroxisome proliferator-activated receptor {gamma} knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 2003.

    Google Scholar 

  157. Argmann CA, Cock TA, Auwerx 1. Peroxisome proliferator-activated receptor gamma: the more the merrier? Eur J Clin Invest 2005; 35:82–92; discussion at 80.

    CAS  PubMed  Google Scholar 

  158. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert 1M, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000; 275:16638–16642.

    CAS  PubMed  Google Scholar 

  159. Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPAR-gamma: Effect of PPARaipha activation on abnormal lipid metabolism in liver of Zucker Fatty rats. Diabetes 1998; 47:1841–1847.

    CAS  PubMed  Google Scholar 

  160. Hegarty BD, Furler SM, Oakes ND, Kraegen EW, Cooney GJ. Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo: A study using the novel PPARalphalgamma agonist tesaglitazar. Endocrinology 2004; 145:3158–3164.

    CAS  PubMed  Google Scholar 

  161. Ye JM, Iglesias MA, Watson DG, Ellis B, Wood L, Jensen PB, Sorensen RV, Larsen PJ, Cooney GJ, Wassermann K, Kraegen EW. PPARalphalgamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence ofhepatomegaly. Am J Physiol 2003; 284: E531–540.

    CAS  Google Scholar 

  162. Smyth S, Heron A. Diabetes and obesity: The twin epidemics. Nat Med 2006; 12:75–80.

    CAS  PubMed  Google Scholar 

  163. Barish GD, Narkar VA, Evans RM. PPAR delta: A dagger in the heart of the metabolic syndrome. J Clin Invest 2006; 116:590–597.

    CAS  PubMed  Google Scholar 

  164. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 2003; 100:15924–15929.

    CAS  PubMed  Google Scholar 

  165. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, Grimaldi PA. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. Faseb J 2003; 17:2299–2301.

    CAS  PubMed  Google Scholar 

  166. Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeletal muscle. Biochim Biophys Acta 2003; 1633:43–50.

    CAS  PubMed  Google Scholar 

  167. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 2001; 98:5306–5311.

    CAS  PubMed  Google Scholar 

  168. Iglesias MA, Ye JM, Frangioudakis G, Saha A, Tomas E, Ruderman NB, Cooney GJ, Kraegen EW. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin resistant high-fat fed rats. Diabetes 2002; 51:2886–2894.

    CAS  PubMed  Google Scholar 

  169. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108:1167–1174.

    CAS  PubMed  Google Scholar 

  170. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers 0, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51:2074–2081.

    CAS  PubMed  Google Scholar 

  171. Liu Y, Wan Q, Guan Q, Gao L, Zhao J. High-fat diet feeding impairs both the expression and activity of AMPKa in rats’ skeletal muscle. Biochem Biophys Res Commun 2006; 339:701–707.

    CAS  PubMed  Google Scholar 

  172. Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck D1. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol 2006; in press.

    Google Scholar 

  173. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310:1642–1646.

    CAS  PubMed  Google Scholar 

  174. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001; 291:2613–2616.

    CAS  PubMed  Google Scholar 

  175. Harwood HJ Jr, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, Magee WP, Dalvie DK, Soliman VF, Martin WH, Mularski CJ, Eisenbeis SA. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inihibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem 2003; 278:37099–37111.

    CAS  PubMed  Google Scholar 

  176. Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, Bhanot S, Monia BP, Shulman GI. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 2006; 116(3):817–824.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales, Australia

    E. W. Kraegen PhD (Professor and Head of Diabetes Group), G. J. Cooney, Jiming M. Ye PhD (Senior Research Officer of Kraegen Research Group) & Stuart M. Furler PhD (Senior Research Officer of Kraegen Research Group)

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  1. E. W. Kraegen PhD
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  2. G. J. Cooney
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  3. Jiming M. Ye PhD
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  1. Obesity, Diabetes, and Aging Research Center, University of South Florida College of Medicine, Tampa, FL

    Barbara Caleen Hansen PhD (Professor of Internal Medicine and Pediatrics Director) (Professor of Internal Medicine and Pediatrics Director)

  2. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA

    George A. Bray MD (Boyd Professor) (Boyd Professor)

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Kraegen, E.W., Cooney, G.J., Ye, J.M., Furler, S.M. (2008). Fat Feeding and Muscle Fat Deposition Eliciting Insulin Resistance. In: Hansen, B.C., Bray, G.A. (eds) The Metabolic Syndrome. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60327-116-5_16

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