1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.

2. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-543.

3. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 2000;11(6):212-217.

4. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312.

5. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997;389:610-614.

6. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7(8):941-946.

7. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997;389:610-614.

8. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. NatMed 2005;11:183-190.

9. Yang Q, Graham TE, Mody N, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356-362.

10. Ross SR, Graves RA, Spiegelman BM. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity. Genes Dev 1993;7:1318-1324.

11. Moitra J, Mason MM, Olive M, et al. Life without white fat: a transgenic mouse. Genes Dev 1998;12:3168-3181.

12. Shimomura I, Hammer RE, Richardson JA, et al. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998;12:3182-3194.

13. Reitman ML, Gavrilova O. A-ZIP/F-1 mice lacking white fat: a model for understanding lipoatrophic diabetes. Int J Obes Relat Metab Disord 2000;24 Suppl 4:S11-S14.

14. Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000 Feb;105(3):271-278.

15. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999;401:73-76.

16. Ebihara K, Ogawa Y, Masuzaki H, et al. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 2001;50:1440-1448.

17. Colombo C, Cutson JJ, Yamauchi T, et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 2002;51:2727-2733.

18. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570-578.

19. Abel ED, Peroni O, Kim JK, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001;409:729-733.

20. Sivitz WI, DeSautel SL, Kayano T, Bell GI, Pessin JE. Regulation of glucose transporter messenger-RNA in insulin-deficient states. Nature 1989;340:72-74.

21. Muoio DM, Newgard CB. Metabolism: A is for adipokine. Nature 2005;436:337-338.

22. An J, Muoio DM, Shiota M, et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 2004;10:268-274.

23. Ntambi JM, Miyazaki M, Stoehr JP, et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA 2002;99:11482-11486.

24. Cohen P, Miyazaki M, Socci ND, et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 2002;297:240-243.

25. Dobrzyn P, Dobrzyn A, Miyazaki M, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci USA 2004;101:6409-6414.

26. Hulver MW, Berggren JR, Carper MJ, et al. Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans. Cell Metab 2005;2:251-261.

27. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111-1119.

28. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673-1677.

29. Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001;108:437-446.

30. Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005;11: 191-198.

31. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306: 457-461.

32. 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;1:785-789.

33. Frayn KN. The glucose-fatty acid cycle: a physiological perspective. Biochem Soc Trans 2003;31:1115-1119.

34. McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 1977;60:265-270.

35. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002;51:7-18.

36. Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 2003;144:5166-5171.

37. Saha AK, Ruderman NB. Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol Cell Biochem 2003;253: 65-70.

38. 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;291:2613-2166.

39. Hulver MW, Berggren JR, Cortright RN, et al. Skeletal muscle lipid metabolism with obesity. Am J Physiol Endocrinol Metab 2003;284:E741-E747.

40. Griffin ME, Marcucci MJ, Cline et al. 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.

41. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333-336.

42. Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord 2003;27 Suppl 3:S6-11.

43. Saltiel AR, Pessin JE. Insulin signaling pathways in time and space. Trends Cell Biol 2002;12:65-71.

44. Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 2003;27 Suppl 3:S49-52.

45. Houmard JA, Tanner CJ, Yu C, et al. Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects. Diabetes 2002;51:2959-2963.

46. Summers SA, Nelson DH. A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing's syndrome. Diabetes 2005;54:591-602.

47. Chavez JA, Holland WL, Bar J, Sandhoff K, Summers SA. Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. J Biol Chem 2005;280:20148-20153.

48. Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys 2003;419:101-109.

49. Helge JW, Dobrzyn A, Saltin B, Gorski J. Exercise and training effects on ceramide metabolism in human skeletal muscle. Exp Physiol 2004;89:119-127.

50. Chavez JA, Knotts TA, Wang LP, et al. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 2003;278:10297-10303.

51. 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.

52. Ruderman NB, Cacicedo JM, Itani S, et al. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem Soc Trans 2003;31:202-206.

53. Rasmussen BB, Holmback UC, Volpi E, Morio-Liondore B, Paddon-Jones D, Wolfe RR. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J Clin Invest 2002;110:1687-1693.

54. Bavenholm PN, Kuhl J, Pigon J, Saha AK, Ruderman NB, Efendic S. Insulin resistance in type 2 diabetes: association with truncal obesity, impaired fitness, and atypical malonyl coenzyme A regulation. J Clin Endocrinol Metab 2003;88:82-87.

55. Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002;277:50230-50236.

56. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 2000;49:677-683.

57. Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol 1999;277:E1130-E1141.

58. Blaak EE. Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus. Proc Nutr Soc 2004;63:323-330.

59. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347:645-650.

60. Gilde AJ, Van Bilsen M. Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiol Scand 2003;178:425-434.

61. Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA 1999;96:7473-7478.

62. Rosen ED, Sarraf P, Troy AE, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611-617.

63. Norris AW, Chen L, Fisher SJ, et al. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest 2003;112:608-618.

64. Muoio DM, MacLean PS, Lang DB, et al. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J Biol Chem 2002;277:26089-26097.

65. Wang YX, Zhang CL, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004;2:e294.

66. Yechoor VK, Patti ME, Saccone R, Kahn CR. Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice. Proc Natl Acad Sci USA 2002;99:10587-10592.

67. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829-839.

68. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003;24:78-90.

69. Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002;418:797-801.

70. Mootha VK, Handschin C, Arlow D, et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 2004;101:6570-6575.

71. Koves TR, Li P, An J, et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 2005;280:33588-33598.

72. Sparks LM, Xie H, Koza RA, et al. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phospho-rylation in skeletal muscle. Diabetes 2005;54:1926-1933.

73. Muoio DM, Newgard CB. Obesity-Related Derangements in Metabolic Regulation. Annu Rev Biochem 2006;75:367-401.

4 Fat Metabolism in Insulin Resistance and Type 2 Diabetes



Maintenance of Whole-Body Glucose and FFA Homeostasis General Overview of the Major Organs Involved in Glucose and FFA

Homeostasis and Organ Cross-Talk Abnormalities of FFA Metabolism in Obesity, Insulin Resistance, and Type 2 Diabetes Consequences of Altered Free Fatty Acid Metabolism on Muscle, Liver, and Pancreas Inhibition of Fatty Acid Flux from Adipose Tissue. Is it Effective in Ameliorating the Manifestations of Insulin Resistance and Type 2 Diabetes? Conclusions Acknowledgements References

Key Words: Free fatty acid; insulin resistance; adipocyte; inflammation; fatty acid transporter.

Weight Loss Funnel

Weight Loss Funnel

Who Else Wants To Discover The 3 Most Effective Fat Burning Methods The Weight Loss Industry Does NOT Want You To Know About.

Get My Free Ebook

Post a comment