The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance

Endocrine Reviews

Volumn 31, Issue 1, 2010, Pages 25-51

  Pagel Langenickel, Ines ^a   Bao, Jianjun ^a   Pang, Liyan ^a   Sack, Michael N ^a  

^a NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; [2 METHYL 4 [4 METHYL 2 (4 TRIFLUOROMETHYLPHENYL) 5 THIAZOLYLMETHYLTHIO]PHENOXY]ACETIC ACID; FATTY ACID; GLUCOSE; INSULIN; PIOGLITAZONE; ROSIGLITAZONE; TROGLITAZONE;

BIOGENESIS; CELL DISRUPTION; CLINICAL TRIAL; DISEASE ASSOCIATION; DISEASE COURSE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; GENE DISRUPTION; GENETIC DISORDER; GENETIC PREDISPOSITION; GENETIC VARIABILITY; GLUCOSE TRANSPORT; GLUCOSE UTILIZATION; HOMEOSTASIS; HUMAN; IMMOBILIZATION; IMPAIRED GLUCOSE TOLERANCE; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID STORAGE; METABOLISM; MITOCHONDRION; MOLECULAR BIOLOGY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUTRIENT; OVARY POLYCYSTIC DISEASE; OXIDATIVE PHOSPHORYLATION; PARENT; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SENESCENCE; SKELETAL MUSCLE;

ANIMALS; DIABETES MELLITUS, TYPE 2; HUMANS; INSULIN RESISTANCE; METABOLIC SYNDROME X; MITOCHONDRIA, MUSCLE; MITOCHONDRIAL DISEASES; MUSCLE, SKELETAL; ORGAN SPECIFICITY; PREDIABETIC STATE;

EID: 76149131004     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2009-0003     Document Type: Review

References (262)

1. Reaven GM 1995 Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473-486
2. Fernández-Real JM, Pickup JC 2008 Innate immunity, insulin resistance and type 2 diabetes. Trends Endocrinol Metab 19:10-16
3. Karlsson HK, Ahlsén M, Zierath JR, Wallberg-Henriksson H, Koistinen HA 2006 Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients. Diabetes 55:1283-1288
4. Meyer C, Dostou JM, Welle SL, Gerich JE 2002 Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab 282:E419-E427
5. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG 1990 Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulindependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 322:223-228
6. Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL, Shulman GI 2007 Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56:1376-1381
7. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, MunE, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ 2003 Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 100:8466-8471
8. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI 2004 Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664-671
9. Lowell BB, Shulman GI 2005 Mitochondrial dysfunction and type 2 diabetes. Science 307:384-387
10. Schrauwen-Hinderling VB, Roden M, Kooi ME, Hesselink MK, Schrauwen P 2007 Muscular mitochondrial dysfunction and type 2 diabetes mellitus. Curr Opin Clin Nutr Metab Care 10:698-703
11. Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsøe R, Dela F 2007 Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50:790-796
12. Holloszy JO 2009 Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance.AmJ Clin Nutr 89:463S-466S
13. Kraegen EW, Cooney GJ, Turner N 2008 Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction. Proc Natl Acad Sci USA 105:7627-7628
14. Rabøl R, Boushel R, Dela F 2006 Mitochondrial oxidative function and type 2 diabetes. Appl Physiol Nutr Metab 31:675-683
15. Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm Jr RH, Probstfield JL, Simons-Morton DG, FriedewaldWT2008 Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545-2559
16. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F 2008 Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560-2572
17. Goodarzi MO, Psaty BM 2008 Glucose lowering to control macrovascular disease in type 2 diabetes: treating the wrong surrogate end point? JAMA 300:2051-2053
18. Clementi E, Nisoli E 2005 Nitric oxide and mitochondrial biogenesis: a key to long-term regulation of cellular metabolism. Comp Biochem Physiol A Mol Integr Physiol 142:102-110
19. McLeod CJ, Pagel I, Sack MN 2005 The mitochondrial biogenesis regulatory program in cardiac adaptation to ischemia - a putative target for therapeutic intervention. Trends Cardiovasc Med 15:118-123
20. Cotney J, Wang Z, Shadel GS 2007 Relative abundance of the human mitochondrial transcription system and distinct roles for h-mtTFB1 and h-mtTFB2 in mitochondrial biogenesis and gene expression. Nucleic Acids Res 35:4042-4054
21. Herzig RP, Scacco S, Scarpulla RC 2000 Sequential serumdependent activation of CREB and NRF-1 leads to enhanced mitochondrial respiration through the induction of cytochrome c. J Biol Chem 275:13134-13141
22. Li B, Holloszy JO, Semenkovich CF 1999 Respiratory uncoupling induces δ-aminolevulinate synthase expression through a nuclear respiratory factor-1-dependent mechanism in HeLa cells. J Biol Chem 274:17534-17540
23. Scarpulla RC 2002 Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene 286:81-89
24. Huss JM, Torra IP, Staels B, Giguère V, Kelly DP 2004 Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol 24:9079-9091
25. Huss JM, Kelly DP 2004 Nuclear receptor signaling and cardiac energetics. Circ Res 95:568-578
26. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM 1999 Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115-124
27. St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB, Spiegelman BM 2003 Bioenergetic analysis of peroxisome proliferator-activated receptor γ coactivators 1α and 1β (PGC-1α and PGC-1β) in muscle cells. J Biol Chem 278:26597-26603
28. Lee HC, Yin PH, Lu CY, Chi CW, Wei YH 2000 Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 348:425-432
29. Lynn EG, Lu Z, Minerbi D, Sack MN 2007 The regulation, control, and consequences of mitochondrial oxygen utilization and disposition in the heart and skeletal muscle during hypoxia. Antioxid Redox Signal 9:1353-1361
30. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S, Carruba MO 2003 Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299:896-899
31. Weitzel JM, Iwen KA, Seitz HJ 2003 Regulation of mitochondrial biogenesis by thyroid hormone. Exp Physiol 88:121-128
32. Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO 2008 High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 105:7815-7820
33. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR 2005 A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926-1933
34. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS 2003 Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100:7996-8001
35. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ 2009 Autophagy regulates lipid metabolism. Nature 458:1131-1135
36. Abdul-Ghani MA, DeFronzo RA 2008 Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diab Rep 8:173-178
37. Szendroedi J, Roden M 2008 Mitochondrial fitness and insulin sensitivity in humans. Diabetologia 51:2155-2167
38. Adams 2nd JM, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ 2004 Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53:25-31
39. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI 1999 Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade. Diabetes 48:1270-1274
40. Itani SI, Ruderman NB, Schmieder F, BodenG2002 Lipidinduced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes 51:2005-2011
41. Morino K, Petersen KF, Shulman GI 2006 Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9-S15
42. Petersen KF, Dufour S, Shulman GI 2005 Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med 2:e233
43. Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI 2005 Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115:3587-3593
44. Kemp GJ 2008 The interpretation of abnormal 31P magnetic resonance saturation transfer measurements of Pi/ATP exchange in insulin-resistant skeletal muscle. Am J Physiol Endocrinol Metab 294:E640-E642
45. Daussin FN, Zoll J, Ponsot E, Dufour SP, Doutreleau S, Lonsdorfer E, Ventura-Clapier R, Mettauer B, Piquard F, Geny B, Richard R 2008 Training at high exercise intensity promotes qualitative adaptations of mitochondrial function in human skeletal muscle. J Appl Physiol 104:1436-1441
46. Daussin FN, Zoll J, Dufour SP, Ponsot E, Lonsdorfer-Wolf E, Doutreleau S, Mettauer B, Piquard F, Geny B, Richard R 2008 Effect of interval versus continuous training on cardiorespiratory and mitochondrial functions: relationship to aerobic performance improvements in sedentary subjects. Am J Physiol Regul Integr Comp Physiol 295:R264-R272
47. Nyholm B, Mengel A, Nielsen S, Skjaerbaek C, Møller N, Alberti KG, Schmitz O 1996 Insulin resistance in relatives ofNIDDMpatients: the role of physical fitness and muscle metabolism. Diabetologia 39:813-822
48. Berntorp K, Lindgärde F 1985 Impaired physical fitness and insulin secretion in normoglycaemic subjects with familial aggregation of type 2 diabetes mellitus. Diabetes Res 2:151-156
49. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Lee CD, Blair SN 1999 The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men. Ann Intern Med 130:89-96
50. Booth FW, Laye MJ, Lees SJ, Rector RS, Thyfault JP 2008 Reduced physical activity and risk of chronic disease: the biology behind the consequences. Eur J Appl Physiol 102:381-390
51. Perseghin G, Scifo P, Danna M, Battezzati A, Benedini S, Meneghini E, Del Maschio A, Luzi L 2002 Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation.AmJ Physiol Endocrinol Metab 283:E556-E564
52. Thyfault JP, Kraus RM, Hickner RC, Howell AW, Wolfe RR, Dohm GL 2004 Impaired plasma fatty acid oxidation in extremely obese women. Am J Physiol Endocrinol Metab 287:E1076-E1081
53. Cooney GJ, Thompson AL, Furler SM, Ye J, Kraegen EW 2002 Muscle long-chain acyl CoA esters and insulin resistance. Ann NY Acad Sci 967:196-207
54. Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA 2000 Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 279:E1039-E1044
55. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC 2003 PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267-273
56. Højlund K, Wrzesinski K, Larsen PM, Fey SJ, Roepstorff P, Handberg A, Dela F, Vinten J, McCormack JG, Reynet C, Beck-Nielsen H 2003 Proteome analysis reveals phosphorylation of ATP synthase β-subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 278:10436-10442
57. Mogensen M, Sahlin K, Fernström M, Glintborg D, Vind BF, Beck-Nielsen H, Højlund K 2007 Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56:1592-1599
58. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P, Radda GK, Neubauer S, Clarke K 2003 Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107:3040-3046
59. Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R, Hoeks J, Kooi ME, Moonen-Kornips E, Sels JP, Hesselink MK, Schrauwen P 2008 Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes 57:2943-2949
60. Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P 2007 Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 50:113-120
61. Pagel-Langenickel I, Schwartz DR, Arena RA, Minerbi DC, Johnson DT, Waclawiw MA, Cannon 3rd RO, Balaban RS, Tripodi DJ, Sack MN 2007 A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 293:H2659-H2666
62. Lillioja S, Young AA, Culter CL, Ivy JL, Abbott WG, Zawadzki JK, Yki-Järvinen H, Christin L, Secomb TW, Bogardus C 1987 Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 80:415-424
63. Simoneau JA, Kelley DE 1997 Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J Appl Physiol 83:166-171
64. Sreekumar R, Halvatsiotis P, Schimke JC, Nair KS 2002 Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 51:1913-1920
65. Szendroedi J, Schmid AI, Chmelik M, Toth C, Brehm A, Krssak M, Nowotny P, Wolzt M, Waldhausl W, Roden M 2007 Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med 4:e154
66. Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA 2008 Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57:1166-1175
67. Petersen KF, Dufour S, Feng J, Befroy D, Dziura J, Dalla Man C, Cobelli C, Shulman GI 2006 Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci USA 103:18273-18277
68. Ehrmann DA 2005 Polycystic ovary syndrome. N Engl J Med 352:1223-1236
69. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A 2005 Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 288:E1047-E1054
70. Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, Brusgaard K, Beck-Nielsen H, Højlund K 2007 Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes 56:2349-2355
71. Pagel-Langenickel I, Bao J, Joseph JJ, Schwartz DR, Mantell BS, Xu X, Raghavachari N, Sack MN 2008 PGC-1α integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle. J Biol Chem 283:22464-22472
72. Skov V, Glintborg D, Knudsen S, Tan Q, Jensen T, Kruse TA, Beck-Nielsen H, Højlund K 2008 Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PLoS ONE 3:e2466
73. Orio Jr F, Palomba S, Giallauria F, Colao A, Vigorito C 2007 Impaired cardiopulmonary parameters in young women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 66:152-153
74. Cosar E, Köken G, Sahin FK, Akgün L, Uçok K, Genç A, Yilmazer M 2008 Resting metabolic rate and exercise capacity in women with polycystic ovary syndrome. Int J Gynaecol Obstet 101:31-34
75. Maassen JA, Jahangir Tafrechi RS, JanssenGM, Raap AK, Lemkes HH, 't Hart LM 2006 New insights in the molecular pathogenesis of the maternally inherited diabetes and deafness syndrome. Endocrinol Metab Clin North Am 35:385-396, x-xi
76. Lindroos MM, Majamaa K, Tura A, Mari A, Kalliokoski KK, Taittonen MT, Iozzo P, Nuutila P 2009 m. 3243A>G mutation in mitochondrialDNAleads to decreased insulin sensitivity in skeletal muscle and to progressive β-cell dysfunction. Diabetes 58:543-549
77. Szendroedi J, Schmid AI, Meyerspeer M, Cervin C, Kacerovsky M, Smekal G, Gräser-Lang S, Groop L, Roden M 2009 Impaired mitochondrial function and insulin resistance of skeletal muscle in mitochondrial diabetes. Diabetes Care 32:677-679
78. Wallace DC 2005 A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359-407
79. Sun F, Cui J, Gavras H, Schwartz F 2003 A novel class of tests for the detection of mitochondrial DNA-mutation involvement in diseases. Am J Hum Genet 72:1515-1526
80. Irwin JA, Saunier JL, Niederstätter H, Strouss KM, Sturk KA, Diegoli TM, Brandstätter A, Parson W, Parsons TJ 2009 Investigation of heteroplasmy in the human mitochondrial DNA control region: a synthesis of observations from more than 5000 global population samples. J Mol Evol 68:516-527
81. Pravenec M, Hyakukoku M, Houstek J, Zidek V, Landa V, Mlejnek P, Miksik I, Dudová-Mothejzikova K, Pecina P, Vrbacky M, Drahota Z, Vojtiskova A, Mracek T, Kazdova L, Oliyarnyk O, Wang J, Ho C, Qi N, Sugimoto K, Kurtz T 2007 Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains. Genome Res 17:1319-1326
82. Hossain P, Kawar B, El Nahas M 2007 Obesity and diabetes in the developing world - a growing challenge. N Engl J Med 356:213-215
83. Krebs M, Roden M 2004 Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem 11:901-908
84. Brownlee M 2005 The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615-1625
85. Brownlee M 2001 Biochemistry and molecular cell biology of diabetic complications. Nature 414:813-820
86. Rabøl R, Højberg PM, Almdal T, Boushel R, Haugaard SB, Madsbad S, Dela F 2009 Effect of hyperglycemia on mitochondrial respiration in type 2 diabetes. J Clin Endocrinol Metab 94:1372-1378
87. Knoll KE, Pietrusz JL, Liang M 2005 Tissue-specific transcriptome responses in rats with early streptozotocin-induced diabetes. Physiol Genomics 21:222-229
88. Willsky GR, Chi LH, Liang Y, Gaile DP, Hu Z, Crans DC 2006 Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate. Physiol Genomics 26:192-201
89. Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J 2008 Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118:789-800
90. Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR 2004 Distinct pathways of insulinregulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA 101:16525-16530
91. Muoio DM, Koves TR 2007 Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 α: implications for metabolic disease. Appl Physiol Nutr Metab 32:874-883
92. Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Moonen-Kornips E, Schaart G, Mustard KJ, Hardie DG, Saris WH, Nicolay K, Schrauwen P 2005 Intramyocellular lipid content and molecular adaptations in response to a 1-week high-fat diet. Obes Res 13:2088-2094
93. Ghosh S, Kewalramani G, Yuen G, Pulinilkunnil T, An D, Innis SM, Allard MF, Wambolt RB, Qi D, Abrahani A, Rodrigues B 2006 Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary omega-6 polyunsaturated fatty acids. Free Radic Biol Med 41:1413-1424
94. Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E 1998 Peroxidative damage to cardiac mitochondria: cytochrome oxidase and cardiolipin alterations. FEBS Lett 424:155-158
95. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI 2003 Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140-1142
96. Befroy DE, Petersen KF, Dufour S, Mason GF, Rothman DL, Shulman GI 2008 Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurancetrained individuals. Proc Natl Acad Sci USA 105:16701-16706
97. Wibom R, Hultman E, Johansson M, Matherei K, Constantin-Teodosiu D, Schantz PG 1992 Adaptation of mitochondrial ATP production in human skeletal muscle to endurance training and detraining. J Appl Physiol 73:2004-2010
98. Goodpaster BH, He J, Watkins S, Kelley DE 2001 Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755-5761
99. Russell AP, Gastaldi G, Bobbioni-Harsch E, Arboit P, Gobelet C, Dériaz O, Golay A, Witztum JL, Giacobino JP 2003 Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids? FEBS Lett 551:104-106
100. Schrauwen P 2007 High-fat diet, muscular lipotoxicity and insulin resistance. Proc Nutr Soc 66:33-41
101. Schrauwen-Hinderling VB, Hesselink MK, Moonen-Kornips E, Schaart G, Kooi ME, Saris WH, Schrauwen P 2006 Short-term training is accompanied by a down regulation of ACC2 mRNA in skeletal muscle. Int J Sports Med 27:786-791
102. Lu Z, Sack MN 2008 ATF-1 is a hypoxia-responsive transcriptional activator of skeletal muscle mitochondrial-uncoupling protein 3. J Biol Chem 283:23410-23418
103. Sack MN 2006 Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res 72:210-219
104. Abdul-Ghani MA, Muller FL, Liu Y, Chavez AO, Balas B, Zuo P, Chang Z, Tripathy D, Jani R, Molina-Carrion M, Monroy A, Folli F, Van Remmen H, DeFronzo RA 2008 Deleterious action of FA metabolites on ATP synthesis: possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance. Am J Physiol Endocrinol Metab 295:E678-E685
105. Ortenblad N, Mogensen M, Petersen I, Højlund K, Levin K, Sahlin K, Beck-Nielsen H, Gaster M 2005 Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect. Biochim Biophys Acta 1741:206-214
106. Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhäusl W, Roden M 2006 Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 55:136-140
107. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI 1996 Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859-2865
108. Laurent D, Didier L, Yerby B, Yerby B, Deacon R, Gao J 2007 Diet-induced modulation of mitochondrial activity in rat muscle.AmJ Physiol Endocrinol Metab 293:E1169-E1177
109. Toledo FG, Menshikova EV, Azuma K, Radiková Z, Kelley CA, Ritov VB, Kelley DE 2008 Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57:987-994
110. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI 2005 Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54:603-608
111. Hoeks J, Hesselink MK, Russell AP, Mensink M, Saris WH, Mensink RP, Schrauwen P 2006 Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance: acute effect of fatty acids. Diabetologia 49:2419-2426
112. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ 2005 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 280:10290-10297
113. Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A, Quistorff B, Vaag A 2009 Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J Physiol 587:2387-2397
114. de Wilde J, Mohren R, van den Berg S, Boekschoten M, Dijk KW, de Groot P, Müller M, Mariman E, Smit E 2008 Short-term high fat-feeding results in morphological and metabolic adaptations in the skeletal muscle of C57BL/6J mice. Physiol Genomics 32:360-369
115. Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ 2007 Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:2085-2092
116. Garcia-Roves P, Huss JM, HanDH, Hancock CR, Iglesias-Gutierrez E, Chen M, Holloszy JO 2007 Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci USA 104:10709-10713
117. Hoeks J, Briedé JJ, de Vogel J, Schaart G, Nabben M, Moonen-Kornips E, Hesselink MK, Schrauwen P 2008 Mitochondrial function, content and ROS production in rat skeletal muscle: effect of high-fat feeding. FEBS Lett 582:510-516
118. Coll T, Eyre E, Rodríguez-Calvo R, Palomer X, Sánchez RM, Merlos M, Laguna JC, Vázquez-Carrera M 2008 Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem 283:11107-11116
119. Dimopoulos N, Watson M, Sakamoto K, Hundal HS 2006 Differential effects of palmitate and palmitoleate on insulin action and glucose utilization in rat L6 skeletal muscle cells. Biochem J 399:473-481
120. Lee JS, Pinnamaneni SK, Eo SJ, Cho IH, Pyo JH, Kim CK, Sinclair AJ, Febbraio MA, Watt MJ 2006 Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites. J Appl Physiol 100:1467-1474
121. Hommelberg PP, Plat J, Langen RC, Schols AM, Mensink RP 2009 Fatty acid-induced NF-κB activation and insulin resistance in skeletal muscle are chain length dependent. Am J Physiol Endocrinol Metab 296:E114-E120
122. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J 2009 Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58:1509-1517
123. KrebsM, KrssakM, Bernroider E, Anderwald C, Brehm A, Meyerspeer M, Nowotny P, Roth E, Waldhäusl W, Roden M 2002 Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes 51:599-605
124. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA 2008 A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3:e2264
125. Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E 2007 Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:e76
126. Nemoto S, Finkel T 2004 Ageing and the mystery at Arles. Nature 429:149-152
127. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P 2007 Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. EMBO J 26:1913-1923
128. Fontana L, Meyer TE, Klein S, Holloszy JO 2004 Longterm calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA 101:6659-6663
129. Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, Rosner B, Hennekens CH, Speizer FE 1991 Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 338:774-778
130. Manson JE, Nathan DM, Krolewski AS, Stampfer MJ, Willett WC, Hennekens CH 1992 A prospective study of exercise and incidence of diabetes among US male physicians. JAMA 268:63-67
131. Coyle EF, Martin 3rd WH, Sinacore DR, Joyner MJ, Hagberg JM, Holloszy JO 1984 Time course of loss of adaptations after stopping prolonged intense endurance training. J Appl Physiol 57:1857-1864
132. Houston ME, Bentzen H, Larsen H 1979 Interrelationships between skeletal muscle adaptations and performance as studied by detraining and retraining. Acta Physiol Scand 105:163-170
133. Henriksson J, Reitman JS 1977 Time course of changes in human skeletal muscle succinate dehydrogenase and cytochrome oxidase activities and maximal oxygen uptake with physical activity and inactivity. Acta Physiol Scand 99:91-97
134. Bey L, Hamilton MT 2003 Suppression of skeletal muscle lipoprotein lipase activity during physical inactivity: a molecular reason to maintain daily low-intensity activity. J Physiol 551:673-682
135. Hamilton MT, Areiqat E, Hamilton DG, Bey L 2001 Plasma triglyceride metabolism in humans and rats during aging and physical inactivity. Int J Sport Nutr Exerc Metab 11 Suppl:S97-S104
136. Chow LS, Greenlund LJ, Asmann YW, Short KR, McCrady SK, Levine JA, Nair KS 2007 Impact of endurance training on murine spontaneous activity, muscle mitochondrial DNA abundance, gene transcripts, and function. J Appl Physiol 102:1078-1089
137. Kang J, Robertson RJ, Hagberg JM, Kelley DE, Goss FL, DaSilva SG, Suminski RR, Utter AC 1996 Effect of exercise intensity on glucose and insulin metabolism in obese individuals and obese NIDDM patients. Diabetes Care 19:341-349
138. Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM 2005 Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 280:33588-33598
139. Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH 2006 Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 61:534-540
140. Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, Nair KS 2003 Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 52:1888-1896
141. Toledo FG, Menshikova EV, Ritov VB, Azuma K, Radikova Z, DeLany J, Kelley DE 2007 Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 56:2142-2147
142. Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, Li H, Li H, Jiang Y, An Y, Shuai Y, Zhang B, Zhang J, Thompson TJ, Gerzoff RB, Roglic G, Hu Y, Bennett PH 2008 The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 371:1783-1789
143. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S 2005 The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 142:611-619
144. Trenell MI, Hollingsworth KG, Lim EL, Taylor R 2008 Increased daily walking improves lipid oxidation without changes in mitochondrial function in type 2 diabetes. Diabetes Care 31:1644-1649
145. Wisløff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share Q, Fernström M, Rezaei K, Lee SJ, Koch LG, Britton SL 2005 Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307:418-420
146. Yaspelkis 3rd BB, Lessard SJ, Reeder DW, Limon JJ, Saito M, Rivas DA, Kvasha I, Hawley JA 2007 Exercise reverses high-fat diet-induced impairments on compartmentalization and activation of components of the insulin-signaling cascade in skeletal muscle.AmJ Physiol Endocrinol Metab 293:E941-E949
147. Haram PM, Kemi OJ, Lee SJ, Bendheim M∅, Al-Share QY, WaldumHL, Gilligan LJ, Koch LG, Britton SL, Najjar SM, Wisløff U 2009 Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity. Cardiovasc Res 81:723-732
148. Lexell J 1995 Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci Med Sci 50 Spec No: 11-16
149. Karakelides H, Nair KS 2005 Sarcopenia of aging and its metabolic impact. Curr Top Dev Biol 68:123-148
150. DeFronzo RA 1981 Glucose intolerance and aging. Diabetes Care 4:493-501
151. Pani LN, Korenda L, Meigs JB, Driver C, Chamany S, Fox CS, Sullivan L, D'Agostino RB, Nathan DM 2008 Effect of aging on A1C levels in individuals without diabetes: evidence from the Framingham Offspring Study and the National Health and Nutrition Examination Survey 2001-2004. Diabetes Care 31:1991-1996
152. Sasaki A, Suzuki T, Horiuchi N 1982 Development of diabetes in Japanese subjects with impaired glucose tolerance: a seven year follow-up study. Diabetologia 22:154-157
153. Rowe JW, Minaker KL, Pallotta JA, Flier JS 1983 Characterization of the insulin resistance of aging. J Clin Invest 71:1581-1587
154. Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS 2005 Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 102:5618-5623
155. Lanza IR, Short DK, Short KR, Raghavakaimal S, Basu R, Joyner MJ, McConnell JP, Nair KS 2008 Endurance exercise as a countermeasure for aging. Diabetes 57:2933-2942
156. Iossa S, Mollica MP, Lionetti L, Crescenzo R, Tasso R, Liverini G 2004 A possible link between skeletal muscle mitochondrial efficiency and age-induced insulin resistance. Diabetes 53:2861-2866
157. Reznick RM, Zong H, Li J, Morino K, Moore IK, Yu HJ, Liu ZX, Dong J, Mustard KJ, Hawley SA, Befroy D, Pypaert M, Hardie DG, Young LH, Shulman GI 2007 Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 5:151-156
158. Barroso I, Luan J, Sandhu MS, Franks PW, Crowley V, Schafer AJ, O'Rahilly S, Wareham NJ 2006 Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 49:501-505
159. Franks PW, Barroso I, Luan J, Ekelund U, Crowley VE, Brage S, Sandhu MS, Jakes RW, Middelberg RP, Harding AH, Schafer AJ, O'Rahilly S, Wareham NJ 2003 PGC-1α genotype modifies the association of volitional energy expenditure with VO2max. Med Sci Sports Exerc 35:1998-2004
160. O'Rahilly S, Barroso I, Wareham NJ 2005 Genetic factors in type 2 diabetes: the end of the beginning? Science 307:370-373
161. Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM 2001 Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 98:3820-3825
162. Benton CR, Nickerson JG, Lally J, Han XX, Holloway GP, Glatz JF, Luiken JJ, Graham TE, Heikkila JJ, Bonen A 2008 Modest PGC-1α overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria. J Biol Chem 283:4228-4240
163. Miura S, Kai Y, Ono M, Ezaki O 2003 Overexpression of peroxisome proliferator-activated receptor γ coactivator-1αdown-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem 278:31385-31390
164. Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang YJ, Liu ZX, Lee HY, Distefano A, Samuel VT, Zhang D, Cline GW, Handschin C, Lin J, Petersen KF, Spiegelman BM, Shulman GI 2008 Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci USA 105:19926-19931
165. Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, Neubauer N, Hu J, Mootha VK, Kim YB, Kulkarni RN, Shulman GI, Spiegelman BM 2007 Abnormal glucose homeostasis in skeletal muscle-specific PGC-1α knockout mice reveals skeletal muscle-pancreatic βcell crosstalk. J Clin Invest 117:3463-3474
166. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM 2007 Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals. J Biol Chem 282:30014-30021
167. Wredenberg A, Freyer C, Sandström ME, Katz A, Wibom R, Westerblad H, Larsson NG 2006 Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem Biophys Res Commun 350:202-207
168. Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP 2005 A potential link between muscle peroxisome proliferator-activated receptor-α signaling and obesity related diabetes. Cell Metab 1:133-144
169. Vahsen N, Candé C, Brière JJ, Bénit P, Joza N, Larochette N, Mastroberardino PG, PequignotMO, Casares N, Lazar V, Feraud O, Debili N, Wissing S, Engelhardt S, Madeo F, Piacentini M, Penninger JM, Schägger H, Rustin P, Kroemer G2004 AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679-4689
170. Joza N, Oudit GY, Brown D, Bénit P, Kassiri Z, Vahsen N, Benoit L, Patel MM, Nowikovsky K, Vassault A, Backx PH, Wada T, Kroemer G, Rustin P, Penninger JM 2005 Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy. Mol Cell Biol 25:10261-10272
171. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G 1999 Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441-446
172. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, Ebersberger I, Nakashima T, Sarao R, Neely G, Esterbauer H, Kozlov A, Kahn CR, Kroemer G, Rustin P, Burcelin R, Penninger JM 2007 Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476-491
173. Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B 2001 Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142:4195-4202
174. Evans RM, Barish GD, Wang YX 2004 PPARs and the complex journey to obesity. Nat Med 10:355-361
175. Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM 2006 PPARδ regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA 103:3444-3449
176. Schuler M, Ali F, Chambon C, Duteil D, Bornert JM, Tardivel A, Desvergne B, Wahli W, Chambon P, Metzger D 2006 PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab 4:407-414
177. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM 2004 Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biol 2:e294
178. Wang H, Knaub LA, Jensen DR, Young Jung D, Hong EG, Ko HJ, Coates AM, Goldberg IJ, de la Houssaye BA, Janssen RC, McCurdy CE, Rahman SM, Soo Choi C, Shulman GI, Kim JK, Friedman JE, Eckel RH 2009 Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues. Diabetes 58:116-124
179. Corpeleijn E, PelsersMM, Soenen S, Mensink M, Bouwman FG, Kooi ME, Saris WH, Glatz JF, Blaak EE 2008 Insulin acutely upregulates protein expression of the fatty acid transporter CD36 in human skeletal muscle in vivo. J Physiol Pharmacol 59:77-83
180. Wu Q, Ortegon AM, Tsang B, Doege H, Feingold KR, Stahl A 2006 FATP1 is an insulin-sensitive fatty acid transporter involved in diet-induced obesity. Mol Cell Biol 26:3455-3467
181. Coburn CT, Knapp Jr FF, Febbraio M, Beets AL, Silverstein RL, Abumrad NA 2000 Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275:32523-32529
182. Hajri T, Han XX, Bonen A, Abumrad NA 2002 Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest 109:1381-1389
183. Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI 2007 Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 117:739-745
184. Ikeda S, Miyazaki H, Nakatani T, Kai Y, Kamei Y, Miura S, Tsuboyama-Kasaoka N, Ezaki O 2002 Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training. Biochem Biophys Res Commun 296:395-400
185. Liu L, Zhang Y, Chen N, Shi X, Tsang B, Yu YH 2007 Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fatinduced insulin resistance. J Clin Invest 117:1679-1689
186. Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, Pulawa LK, McGuire JG, Pitas RE, Eckel RH, Farese Jr RV 2002 Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109:1049-1055
187. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E, Tow B, Sanan DA, Raber J, Eckel RH, Farese Jr RV 2000 Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 25:87-90
188. Jeukendrup AE 2002 Regulation of fat metabolism in skeletal muscle. Ann NY Acad Sci 967:217-235
189. Kiens B 2006 Skeletal muscle lipid metabolism in exercise and insulin resistance. Physiol Rev 86:205-243
190. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM 2008 Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45-56
191. Bruce CR, HoyAJ, Turner N, Watt MJ, Allen TL, Carpenter K, Cooney GJ, Febbraio MA, Kraegen EW 2009 Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes 58:550-558
192. Perdomo G, Commerford SR, Richard AM, Adams SH, Corkey BE, O'Doherty RM, Brown NF 2004 Increased β-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation. J Biol Chem 279:27177-27186
193. Dyck JR, Hopkins TA, Bonnet S, Michelakis ED, Young ME, Watanabe M, Kawase Y, Jishage K, Lopaschuk GD 2006 Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114:1721-1728
194. Krauss S, Zhang CY, Lowell BB 2005 The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6:248-261
195. Stuart JA, Brindle KM, Harper JA, Brand MD 1999 Mitochondrial proton leak and the uncoupling proteins. J Bioenerg Biomembr 31:517-525
196. Brand MD, Esteves TC 2005 Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2:85-93
197. Schrauwen P, Hoeks J, Hesselink MK 2006 Putative function and physiological relevance of the mitochondrial uncoupling protein-3: involvement in fatty acid metabolism? Prog Lipid Res 45:17-41
198. Bézaire V, Hofmann W, Kramer JK, Kozak LP, Harper ME 2001 Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(-/-) and wild-type mice. Am J Physiol Endocrinol Metab 281:E975-E982
199. Boss O, Hagen T, Lowell BB 2000 Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49:143-156
200. Schrauwen P, Mensink M, Schaart G, Moonen-Kornips E, Sels JP, Blaak EE, Russell AP, Hesselink MK 2006 Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients: restoration by rosiglitazone treatment. J Clin Endocrinol Metab 91:1520-1525
201. Jones TE, Baar K, Ojuka E, Chen M, Holloszy JO 2003 Exercise induces an increase in muscle UCP3 as a component of the increase in mitochondrial biogenesis. Am J Physiol Endocrinol Metab 284:E96-E101
202. Mensink M, Hesselink MK, Borghouts LB, Keizer H, Moonen-Kornips E, Schaart G, Blaak EE, Schrauwen P 2007 Skeletal muscle uncoupling protein-3 restores upon intervention in the prediabetic and diabetic state: implications for diabetes pathogenesis? Diabetes Obes Metab 9:594-596
203. García-Martinez C, Sibille B, Solanes G, Darimont C, Macé K, Villarroya F, Gómez-Foix AM 2001 Overexpression of UCP3 in cultured human muscle lowers mitochondrial membrane potential, raises ATP/ADP ratio, and favors fatty acid vs. glucose oxidation. FASEB J 15:2033-2035
204. Mills EM, Banks ML, Sprague JE, Finkel T 2003 Pharmacology: uncoupling the agony from ecstasy. Nature 426:403-404
205. Clapham JC, Arch JR, Chapman H, Haynes A, Lister C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA, Beeley LJ, Godden RJ, Herrity N, Skehel M, Changani KK, Hockings PD, Reid DG, Squires SM, Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ, Cadenas S, Buckingham JA, Brand MD, Abuin A 2000 Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406:415-418
206. Choi CS, Fillmore JJ, Kim JK, Liu ZX, Kim S, Collier EF, Kulkarni A, Distefano A, Hwang YJ, Kahn M, Chen Y, Yu C, Moore IK, Reznick RM, Higashimori T, Shulman GI 2007 Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest 117:1995-2003
207. Schrauwen P, Hardie DG, Roorda B, Clapham JC, Abuin A, Thomason-Hughes M, Green K, Frederik PM, Hesselink MK 2004 Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase? Int J Obes Relat Metab Disord 28:824-828
208. Costford SR, Chaudhry SN, Crawford SA, Salkhordeh M, Harper ME 2008 Long-term high-fat feeding induces greater fat storage in mice lacking UCP3. Am J Physiol Endocrinol Metab 295:E1018-E1024
209. Han DH, Nolte LA, Ju JS, Coleman T, Holloszy JO, Semenkovich CF 2004 UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction. Am J Physiol Endocrinol Metab 286:E347-E353
210. Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF 2007 Respiratory uncoupling in skeletal muscle delays death and diminishes age-related disease. Cell Metab 6:497-505
211. Neschen S, Katterle Y, Richter J, Augustin R, Scherneck S, Mirhashemi F, Schürmann A, Joost HG, Klaus S 2008 Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo. Physiol Genomics 33:333-340
212. Charron MJ, Brosius 3rd FC, Alper SL, Lodish HF 1989 A glucose transport protein expressed predominately in insulin-responsive tissues. Proc Natl Acad Sci USA 86:2535-2539
213. Kahn BB, Rossetti L, Lodish HF, Charron MJ 1991 Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats. J Clin Invest 87:2197-2206
214. King PA, Horton ED, Hirshman MF, Horton ES 1992 Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation. J Clin Invest 90:1568-1575
215. Katz EB, Stenbit AE, Hatton K, DePinho R, Charron MJ 1995 Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377:151-155
216. Stenbit AE, Burcelin R, Katz EB, Tsao TS, Gautier N, Charron MJ, Le Marchand-Brustel Y 1996 Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. J Clin Invest 98:629-634
217. Ranalletta M, Jiang H, Li J, Tsao TS, Stenbit AE, Yokoyama M, Katz EB, Charron MJ 2005 Altered hepatic and muscle substrate utilization provoked by GLUT4 ablation. Diabetes 54:935-943
218. Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL, Factor SM, Houseknecht K, Katz EB, Charron MJ 1997 GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 3:1096-1101
219. Tsao TS, Stenbit AE, Factor SM, Chen W, Rossetti L, Charron MJ 1999 Prevention of insulin resistance and diabetes in mice heterozygous for GLUT4 ablation by transgenic complementation of GLUT4 in skeletal muscle. Diabetes 48:775-782
220. Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton JA, Ouchi N, LeBrasseur NK, Walsh K 2008 Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab 7:159-172
221. Pedersen BK, AkerströmTC, Nielsen AR, Fischer CP 2007 Role of myokines in exercise and metabolism. J Appl Physiol 103:1093-1098
222. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K 2008 FGF21 is an Akt-regulated myokine. FEBS Lett 582:3805-3810
223. Walsh K 2009 Adipokines, myokines and cardiovascular disease. Circ J 73:13-18
224. Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Rydén M 2008 FGF21 attenuates lipolysis in human adipocytes - a possible link to improved insulin sensitivity. FEBS Lett 582:1725-1730
225. WenteW, EfanovAM, BrennerM, Kharitonenkov A, Köster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J 2006 Fibroblast growth factor-21 improves pancreatic β-cell function and survival by activation of extracellular signalregulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470-2478
226. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Véniant MM 2009 Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250-259
227. Boden G, Homko C, Mozzoli M, Showe LC, Nichols C, Cheung P 2005 Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients. Diabetes 54:880-885
228. Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, Straubhaar J, Czech MP, Corvera S 2004 Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 114:1281-1289
229. Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR 2005 Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90:6650-6656
230. Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, Sawada H 2000 Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys ResCommun278:704-711
231. Cha BS, Ciaraldi TP, Park KS, Carter L, Mudaliar SR, Henry RR 2005 Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARγ agonists. Am J Physiol Endocrinol Metab 289:E151-E159
232. Wilmsen HM, Ciaraldi TP, Carter L, Reehman N, Mudaliar SR, Henry RR 2003 Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects. Am J Physiol Endocrinol Metab 285:E354-E362
233. Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, Yano W, Ogata H, Tokuyama K, Takamoto I, Mineyama T, Ishikawa M, Moroi M, Sugi K, Yamauchi T, Ueki K, Tobe K, Noda T, Nagai R, Kadowaki T 2006 Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem 281:8748-8755
234. Mensink M, Hesselink MK, Russell AP, Schaart G, Sels JP, Schrauwen P 2007 Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 α and PPAR β/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. Int J Obes (Lond) 31:1302-1310
235. Hällsten K, Virtanen KA, Lönnqvist F, SipiläH, Oksanen A, Viljanen T, Rönnemaa T, Viikari J, Knuuti J, Nuutila P 2002 Rosiglitazone but not metformin enhances insulinand exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Diabetes 51:3479-3485
236. Schrauwen-Hinderling VB, Mensink M, Hesselink MK, Sels JP, Kooi ME, Schrauwen P 2008 The insulin-sensitizing effect of rosiglitazone in type 2 diabetes mellitus patients does not require improved in vivo muscle mitochondrial function. J Clin Endocrinol Metab 93:2917-2921
237. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T 2008 Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135:100-110
238. Ravikumar B, Gerrard J, Dalla Man C, Firbank MJ, Lane A, English PT, Cobelli C, Taylor R 2008 Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content. Diabetes 57:2288-2295
239. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR 2006 Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096-1105
240. Psaty BM, Furberg CD 2007 Rosiglitazone and cardiovascular risk. N Engl J Med 356:2522-2524
241. Wan Y, Chong LW, Evans RM 2007 PPAR-γ regulates osteoclastogenesis in mice. Nat Med 13:1496-1503
242. Oliver Jr WR, 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, WillsonTM2001Aselective peroxisome proliferatoractivated receptor δ agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98:5306-5311
243. Risérus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum JC, Basu S, Cheeseman J, Fielding BA, Humphreys SM, Danoff T, Moore NR, Murgatroyd P, O'Rahilly S, Sutton P, Willson T, Hassall D, Frayn KN, Karpe F 2008 Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57:332-339
244. Krämer DK, Al-Khalili L, Guigas B, Leng Y, Garcia-Roves PM, Krook A 2007 Role of AMP kinase and PPARδ in the regulation of lipid and glucose metabolism in human skeletal muscle. J Biol Chem 282:19313-19320
245. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA 2004 Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390-392
246. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P 2005 Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434:113-118
247. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA 2003 Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191-196
248. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA 2006 Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-342
249. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J 2006 Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127:1109-1122
250. Doré S 2005 Unique properties of polyphenol stilbenes in the brain: more than direct antioxidant actions; gene/protein regulatory activity. Neurosignals 14:61-70
251. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M 2008 SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283:20015-20026
252. Koo SH, Montminy M 2006 In vino veritas: a tale of two sirt1s? Cell 127:1091-1093
253. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA 2006 Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180-2191
254. Elliott PJ, Jirousek M 2008 Sirtuins: novel targets for metabolic disease. Curr Opin Investig Drugs 9:371-378
255. Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J 2008 Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 8:347-358
256. Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, NgPY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH 2007 Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450:712-716
257. Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q 2007 SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab 6:307-319
258. Hui X, Zhu W, Wang Y, Lam KS, Zhang J, Wu D, Kraegen EW, Li Y, Xu A 2009 Major urinary protein-1 increases energy expenditure and improves glucose intolerance through enhancing mitochondrial function in skeletal muscle of diabetic mice. J Biol Chem 284:14050-14057
259. Keller MP, Choi Y, Wang P, Davis DB, Rabaglia ME, Oler AT, Stapleton DS, Argmann C, Schueler KL, Edwards S, Steinberg HA, Chaibub Neto E, Kleinhanz R, Turner S, Hellerstein MK, Schadt EE, Yandell BS, Kendziorski C, Attie AD 2008 A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res 18:706-716
260. Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, Cline GW, Befroy D, Zemany L, Kahn BB, Papademetris X, Rothman DL, Shulman GI 2007 The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci USA 104:12587-12594
261. Racette SB, Weiss EP, Villareal DT, Arif H, Steger-May K, Schechtman KB, Fontana L, Klein S, Holloszy JO 2006 One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci 61:943-950
262. Larson-Meyer DE, Newcomer BR, Heilbronn LK, Volaufova J, Smith SR, Alfonso AJ, Lefevre M, Rood JC, Williamson DA, Ravussin E 2008 Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity (Silver Spring) 16:1355-1362