Re-evaluating lipotoxic triggers in skeletal muscle: Relating intramyocellular lipid metabolism to insulin sensitivity

Progress in Lipid Research

Volumn 51, Issue 1, 2012, Pages 36-49

  Bosma, Madeleen ^a   Kersten, Sander ^b   Hesselink, Matthijs K C ^a   Schrauwen, Patrick ^a  

^a MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

^b WAGENINGEN UNIVERSITY   (Netherlands)

Author keywords

Athlete's paradox; Ceramide; Diacylglycerol; Lipid droplets; Lipotoxicity; Type 2 diabetes

Indexed keywords

ACYL COENZYME A; ACYL COENZYME A DESATURASE; ACYLCARNITINE; DIACYLGLYCEROL; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 2; FAT DROPLET; INSULIN; PERILIPIN; SPHINGOLIPID; STEAROYL COENZYME A DESATURASE 1; STEAROYL COENZYME A DESATURASE 5; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

CELL INTERACTION; CELLULAR DISTRIBUTION; DISEASE ASSOCIATION; ENZYME ACTIVATION; ENZYME DEGRADATION; ENZYME PHOSPHORYLATION; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTRACELLULAR MEMBRANE; INTRACELLULAR SIGNALING; LIPID BLOOD LEVEL; LIPID COMPOSITION; LIPID METABOLISM; LIPID OXIDATION; LIPID STORAGE; LIPOGENESIS; LIPOTOXICITY; MOLECULAR DYNAMICS; MUSCLE METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PARTICLE SIZE; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LIPID INTERACTION; REVIEW; SEX DIFFERENCE; SKELETAL MUSCLE;

ANIMALS; HUMANS; INSULIN; LIPID METABOLISM; MUSCLE PROTEINS; MUSCLE, SKELETAL;

EID: 83455229494     PISSN: 01637827     EISSN: 18732194     Source Type: Journal    
DOI: 10.1016/j.plipres.2011.11.003     Document Type: Review

References (172)

1. WHO. Obesity and overweight - Fact sheet N 311. 2011.
2. D.E. Lee, S. Kehlenbrink, H. Lee, M. Hawkins, and J.S. Yudkin Getting the message across: mechanisms of physiological cross talk by adipose tissue Am J Physiol Endocrinol Metab 296 2009 E1210 E1229
3. J.D. McGarry What if Minkowski had been ageusic? An alternative angle on diabetes Science 258 1992 766 770
4. N.G. Forouhi, G. Jenkinson, E.L. Thomas, S. Mullick, S. Mierisova, and U. Bhonsle Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men Diabetologia 42 1999 932 935 (Pubitemid 29369600)
5. J. Machann, O.P. Bachmann, K. Brechtel, D.B. Dahl, B. Wietek, and B. Klumpp Lipid content in the musculature of the lower leg assessed by fat selective MRI: Intra- and interindividual differences and correlation with anthropometric and metabolic data J Magn Reson Imaging 17 2003 350 357 (Pubitemid 36259250)
6. A. Misra, S. Sinha, M. Kumar, N.R. Jagannathan, and R.M. Pandey Proton magnetic resonance spectroscopy study of soleus muscle in non-obese healthy and type 2 diabetic Asian Northern Indian males: high intramyocellular lipid content correlates with excess body fat and abdominal obesity Diabet Med 20 2003 361 367 (Pubitemid 36605620)
7. C. Moro, J.E. Galgani, L. Luu, M. Pasarica, A. Mairal, and S. Bajpeyi Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals J Clin Endocrinol Metab 94 2009 3440 3447
8. R. Sinha, S. Dufour, K.F. Petersen, V. LeBon, S. Enoksson, and Y.-Z. Ma Assessment of skeletal muscle triglyceride content by 1H nuclear magnetic resonance spectroscopy in lean and obese adolescents Diabetes 51 2002 1022 1027
9. C. Aguer, J. Mercier, C. Yong Wai Man, L. Metz, S. Bordenave, and K. Lambert Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients Diabetologia 53 2010 1151 1163
10. B.H. Goodpaster, R. Theriault, S.C. Watkins, and D.E. Kelley Intramuscular lipid content is increased in obesity and decreased by weight loss Metabolism 49 2000 467 472 (Pubitemid 30196572)
11. D.A. Pan, S. Lillioja, A.D. Kriketos, M.R. Milner, L.A. Baur, and C. Bogardus Skeletal muscle triglyceride levels are inversely related to insulin action Diabetes 46 1997 983 988 (Pubitemid 27220998)
12. R.E. Gray, C.J. Tanner, W.J. Pories, K.G. MacDonald, and J.A. Houmard Effect of weight loss on muscle lipid content in morbidly obese subjects Am J Physiol Endocrinol Metab 284 2003 E726 E732
13. I. Jazet, G. Schaart, A. Gastaldelli, E. Ferrannini, M. Hesselink, and P. Schrauwen Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients Diabetologia 51 2008 309 319
14. T.P.J. Solomon, S.N. Sistrun, R.K. Krishnan, L.F. Del Aguila, C.M. Marchetti, and S.M. O'Carroll Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults J Appl Physiol 104 2008 1313 1319
15. Y. Tamura, Y. Tanaka, F. Sato, J.B. Choi, H. Watada, and M. Niwa Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients J Clin Endocrinol Metab 90 2005 3191 3196 (Pubitemid 41014274)
16. F.G.S. Toledo, E.V. Menshikova, K. Azuma, Z. Radiková, C.A. Kelley, and V.B. Ritov Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content Diabetes 57 2008 987 994
17. O.P. Bachmann, D.B. Dahl, K. Brechtel, Machann Jr., M. Haap, and T. Maier Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans Diabetes 50 2001 2579 2584 (Pubitemid 33642777)
18. L.J.C. Van Loon, R. Koopman, R. Manders, W. van der Weegen, G.P. van Kranenburg, and H.A. Keizer Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes Am J Physiol Endocrinol Metab 287 2004 E558 E565
19. V. Schrauwen-Hinderling, M. Kooi, M. Hesselink, J. Jeneson, W. Backes, and C. van Echteld Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects Diabetologia 50 2007 113 120 (Pubitemid 46035859)
20. B.H. Goodpaster, J. He, S. Watkins, and D.E. Kelley Skeletal muscle lipid content and insulin resistance. evidence for a paradox in endurance-trained athletes J Clin Endocrinol Metab 86 2001 5755 5761 (Pubitemid 33152620)
21. J.J. Dubé, F. Amati, M. Stefanovic-Racic, F.G.S. Toledo, S.E. Sauers, and B.H. Goodpaster Exercise-induced alterations in intramyocellular lipids and insulin resistance. the athlete's paradox revisited Am J Physiol Endocrinol Metab 294 2008 E882 E888
22. R.C.R. Meex, V.B. Schrauwen-Hinderling, E. Moonen-Kornips, G. Schaart, M. Mensink, and E. Phielix Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training Is paralleled by increased myocellular fat storage and improved insulin sensitivity Diabetes 59 2010 572 579
23. B.C. Bergman, L. Perreault, D.M. Hunerdosse, M.C. Koehler, A.M. Samek, and R.H. Eckel Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes J Appl Physiol 108 2010 1134 1141
24. J.E. Schaffer Lipotoxicity: when tissues overeat Curr Opin Lipidol 14 2003 281 287 (Pubitemid 36688207)
25. L. Liu, X. Shi, C.S. Choi, G.I. Shulman, K. Klaus, and K.S. Nair Paradoxical coupling of triglyceride synthesis and fatty acid oxidation in skeletal muscle overexpressing DGAT1 Diabetes 58 2009 2516 2524
26. S. Timmers, J. den Bosch, M.K.C. Hesselink, D. van Beurden, G. Schaart, and M.J. Ferraz PLoS ONE 6 2011 e14503
27. A.V. Chibalin, Y. Leng, E. Vieira, A. Krook, M. Björnholm, and Y.C. Long Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance Cell 132 2008 375 386 (Pubitemid 351191998)
28. W.J. van Blitterswijk, and B. Houssa Properties and functions of diacylglycerol kinases Cell Signal 12 2000 595 605
29. J.A. Chavez, and S.A. Summers 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 419 2003 101 109 (Pubitemid 37329976)
30. E. Montell, M. Turini, M. Marotta, M. Roberts, V. Noe, and C.J. Ciudad DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells Am J Physiol Endocrinol Metab 280 2001 E229 E237
31. I. Idris, S. Gray, and R. Donnelly Protein kinase C activation: Isozyme-specific effects on metabolism and cardiovascular complications in diabetes Diabetologia 44 2001 659 673 (Pubitemid 32846021)
32. V.T. Samuel, K.F. Petersen, and G.I. Shulman Lipid-induced insulin resistance: unravelling the mechanism The Lancet 375 2010 2267 2277
33. S. Turban, and E. Hajduch Protein kinase C isoforms: mediators of reactive lipid metabolites in the development of insulin resistance FEBS Lett 585 2011 269 274
34. L.T. Boni, and R.R. Rando The nature of protein kinase C activation by physically defined phospholipid vesicles and diacylglycerols J Biol Chem 260 1985 10819 10825 (Pubitemid 16252268)
35. F.M. Goñi, and A. Alonso Structure and functional properties of diacylglycerols in membranes Prog Lipid Res 38 1999 1 48 (Pubitemid 29090112)
36. M.J.O. Wakelam Diacylglycerol - when is it an intracellular messenger? Biochim Biophys Acta 1436 1998 117 126
37. A.K. Saha, T.G. Kurowski, J.R. Colca, and N.B. Ruderman Lipid abnormalities in tissues of the KKAy mouse: effects of pioglitazone on malonyl-CoA and diacylglycerol Am J Physiol Endocrinol Metab 267 1994 E95 E101
38. J. Turinsky, D.M. O'Sullivan, and B.P. Bayly 1, 2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo J Biol Chem 265 1990 16880 16885
39. S.I. Itani, N.B. Ruderman, F. Schmieder, and G. Boden Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkBa Diabetes 51 2002 2005 2011 (Pubitemid 34729001)
40. C. Moro, S. Bajpeyi, and S.R. Smith Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity Am J Physiol Endocrinol Metab 294 2008 E203 E213
41. M. Straczkowski, I. Kowalska, M. Baranowski, A. Nikolajuk, E. Otziomek, and P. Zabielski Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes Diabetologia 50 2007 2366 2373 (Pubitemid 47512392)
42. Jocken JWE, Moro C, Goossens GH, Hansen D, Mairal A, Hesselink MKC, et al. Skeletal muscle lipase content and activity in obesity and type 2 diabetes. J Clin Endocrinol Metab 2010:jc.2010-0776.
43. A.B. Thrush, D.N. Brindley, A. Chabowski, G.J. Heigenhauser, and D.J. Dyck Skeletal muscle lipogenic protein expression is not different between lean and obese individuals: a potential factor in ceramide accumulation J Clin Endocrinol Metab 94 2009 5053 5061
44. C.A. Anastasiou, S.A. Kavouras, Y. Lentzas, A. Gova, L.S. Sidossis, and A. Melidonis Diabetes mellitus is associated with increased intramyocellular triglyceride, but not diglyceride, content in obese humans Metabolism 58 2009 1636 1642
45. P.M. Coen, J.J. Dubé, F. Amati, M. Stefanovic-Racic, R.E. Ferrell, and F.G.S. Toledo Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content Diabetes 59 2009 80 88
46. L. Perreault, B.C. Bergman, D.M. Hunerdosse, M.C. Playdon, and R.H. Eckel Inflexibility in intramuscular triglyceride fractional synthesis distinguishes prediabetes from obesity in humans Obesity 18 2010 1524 1531
47. L. Perreault, B.C. Bergman, D.M. Hunerdosse, and R.H. Eckel Altered intramuscular lipid metabolism relates to diminished insulin action in men, but not women, in progression to diabetes Obesity 18 2010 2093 2100
48. C.R. Bruce, A.B. Thrush, V.A. Mertz, V. Bezaire, A. Chabowski, and G.J.F. Heigenhauser Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content Am J Physiol Endocrinol Metab 291 2006 E99 E107
49. J. Dubé, F. Amati, F. Toledo, M. Stefanovic-Racic, A. Rossi, and P. Coen Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide Diabetologia 2011 1 10
50. M. Bajaj, R. Baig, S. Suraamornkul, L.J. Hardies, D.K. Coletta, and G.W. Cline Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus J Clin Endocrinol Metab 95 2010 1916 1923
51. C.A. Anastasiou, S.A. Kavouras, Y. Lentzas, A. Gova, L.S. Sidossis, and A. Melidonis Moderate weight loss depletes intramyocellular triglycerides but has no effect on diglycerides in type II diabetes Eur J Clin Nutr 64 2010 328 330
52. A.M.J. Van Hees, A. Jans, G.B. Hul, H.M. Roche, W.H.M. Saris, and E.E. Blaak Skeletal muscle fatty acid handling in insulin resistant men Obesity 19 2011 1350 1359
53. L. Kuerschner, C. Moessinger, and C. Thiele Imaging of lipid biosynthesis: how a neutral lipid enters lipid droplets Traffic 9 2008 338 352 (Pubitemid 351188994)
54. C.R. Bruce, A.J. Hoy, N. Turner, M.J. Watt, T.L. Allen, and K. Carpenter 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 2009 550 558
55. C.S. Choi, D.E. Befroy, R. Codella, S. Kim, R.M. Reznick, and Y.-J. Hwang Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism Proc Natl Acad Sci 105 2008 19926 19931
56. C.S. Choi, J.J. Fillmore, J.K. Kim, Z.X. Liu, S. Kim, and E.F. Collier Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance J Clin Invest 117 2007 1995 2003 (Pubitemid 47036334)
57. S.A. Summers Ceramides in insulin resistance and lipotoxicity Prog Lipid Res 45 2006 42 72 (Pubitemid 43170804)
58. A. Blachnio-Zabielska, M. Baranowski, P. Zabielski, and J. Gorski Effect of high fat diet enriched with unsaturated and diet rich in saturated fatty acids on sphingolipid metabolism in rat skeletal muscle J Cell Physiol 225 2010 786 791
59. W.L. Holland, J.T. Brozinick, L.-P. Wang, E.D. Hawkins, K.M. Sargent, and Y. Liu Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance Cell Metab 5 2007 167 179
60. A.H. Merrill De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway J Biol Chem 277 2002 25843 25846
61. S.A. Summers Sphingolipids and insulin resistance. the five Ws Curr Opin Lipidol 21 2010 128 135
62. J.A. Chavez, T.A. Knotts, L.-P. Wang, G. Li, R.T. Dobrowsky, and G.L. Florant A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids J Biol Chem 278 2003 10297 10303 (Pubitemid 36800291)
63. K. Kabayama, T. Sato, K. Saito, N. Loberto, A. Prinetti, and S. Sonnino Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance Proc Natl Acad Sci 104 2007 13678 13683 (Pubitemid 350003380)
64. S.A. Novgorodov, B.X. Wu, T.I. Gudz, J. Bielwaski, T.V. Ovchinnikova, and Y.A. Hannun Novel pathway of ceramide production in mitochondria: Thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-COA J Biol Chem 286 2011 25352 25362
65. J.M. Adams, T. Pratipanawatr, R. Berria, E. Wang, R.A. DeFronzo, and M.C. Sullards Ceramide content is increased in skeletal muscle from obese insulin-resistant humans Diabetes 53 2004 25 31 (Pubitemid 38044694)
66. M.J. Serlie, A.J. Meijer, J.E. Groener, M. Duran, E. Endert, and E. Fliers Short-term manipulation of plasma free fatty acids does not change skeletal muscle concentrations of ceramide and glucosylceramide in lean and overweight subjects J Clin Endocrinol Metab 92 2007 1524 1529 (Pubitemid 46556434)
67. M. Skovbro, M. Baranowski, C. Skov-Jensen, A. Flint, F. Dela, and J. Gorski Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity Diabetologia 51 2008 1253 1260
68. P. Nordby, C. Prats, D. Kristensen, K. Ekroos, G. Forsberg, and J. Andersen Muscle ceramide content in man is higher in type I than type II fibers and not influenced by glycogen content Eur J of Appl Physiol 109 2010 935 943
69. L.D. Hoeg, K.A. Sjoberg, J. Jeppesen, T.E. Jensen, C. Frosig, and J.B. Birk Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling Diabetes 60 2011 64 73
70. M. Straczkowski, I. Kowalska, A. Nikolajuk, S. Dzienis-Straczkowska, I. Kinalska, and M. Baranowski Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle Diabetes 53 2004 1215 1221 (Pubitemid 38569006)
71. B. Vistisen, L.I. Hellgren, T. Vadset, C. Scheede-Bergdahl, W. Helge Jr., and F. Dela Effect of gender on lipid-induced insulin resistance in obese subjects Eur J Endocrinol 158 2008 61 68 (Pubitemid 351211041)
72. B.A. Ellis, A. Poynten, A.J. Lowy, S.M. Furler, D.J. Chisholm, and E.W. Kraegen Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle Am J Physiol Endocrinol Metab 279 2000 E554 E560
73. M.W. Hulver, J.R. Berggren, R.N. Cortright, R.W. Dudek, R.P. Thompson, and W.J. Pories Skeletal muscle lipid metabolism with obesity Am J Physiol Endocrinol Metab 284 2003 E741 E747
74. S.M. Chalkley, M. Hettiarachchi, D.J. Chisholm, and E.W. Kraegen Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat Metabolism 47 1998 1121 1126 (Pubitemid 28428018)
75. C. Yu, Y. Chen, G.W. Cline, D. Zhang, H. Zong, and Y. Wang 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 277 2002 50230 50236 (Pubitemid 36042170)
76. M. Bajaj, S. Suraamornkul, A. Romanelli, G.W. Cline, L.J. Mandarino, and G.I. Shulman 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 54 2005 3148 3153 (Pubitemid 43334368)
77. J.A. Houmard, C.J. Tanner, C. Yu, P.G. Cunningham, W.J. Pories, and K.G. MacDonald Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects Diabetes 51 2002 2959 2963
78. C.R. Bruce, M.J. Anderson, A.L. Carey, D.G. Newman, A. Bonen, and A.D. Kriketos Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status J Clin Endocrinol Metab 88 2003 5444 5451 (Pubitemid 37452752)
79. N.J. Faergeman, and J. Knudsen Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling Biochem J 323 1997 1 12 (Pubitemid 27153867)
80. C.M. Jenkins, J. Yang, H.F. Sims, and R.W. Gross Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA J Biol Chem 286 2011 11937 11950
81. T.R. Koves, J.R. Ussher, R.C. Noland, D. Slentz, M. Mosedale, and O. Ilkayeva Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance Cell Metab 7 2008 45 56
82. S. Violante, L. Ijlst, H. van Lenthe, I.T. de Almeida, R.J. Wanders, and F.V. Ventura Carnitine palmitoyltransferase 2: New insights on the substrate specificity and implications for acylcarnitine profiling Biochim Biophys Acta 1802 2010 728 732
83. Bell JA, Reed MA, Consitt LA, Martin OJ, Haynie KR, Hulver MW, et al. Lipid partitioning, incomplete fatty acid oxidation, and insulin signal transduction in primary human muscle cells: effects of severe obesity, fatty acid incubation, and fatty acid translocase/CD36 overexpression. J Clin Endocrinol Metab 2010:jc.2009-1596.
84. Boyle KE, Canham JP, Consitt LA, Zheng D, Koves TR, Gavin TP, et al. A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals. J Clin Endocrinol Metab 2010:jc.2010-253.
85. M. Gaster Reduced lipid oxidation in myotubes established from obese and type 2 diabetic subjects Biochem Biophys Res Commun 382 2009 766 770
86. A.J. Wensaas, A.C. Rustan, M. Just, R.K. Berge, C.A. Drevon, and M. Gaster Fatty acid incubation of myotubes from humans with type 2 diabetes leads to enhanced release of {beta}-oxidation products because of impaired fatty acid oxidation: effects of tetradecylthioacetic acid and eicosapentaenoic Acid Diabetes 58 2009 527 535
87. K.M. Huffman, S.H. Shah, R.D. Stevens, J.R. Bain, M. Muehlbauer, and C.A. Slentz Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women Diabetes Care 32 2009 1678 1683
88. C.B. Newgard, J. An, J.R. Bain, M.J. Muehlbauer, R.D. Stevens, and L.F. Lien A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance Cell Metab 9 2009 311 326
89. S.H. Adams, C.L. Hoppel, K.H. Lok, L. Zhao, S.W. Wong, and P.E. Minkler Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women J Nutr 139 2009 1073 1081
90. S.J. Mihalik, B.H. Goodpaster, D.E. Kelley, D.H. Chace, J. Vockley, and F.G.S. Toledo Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity Obesity 18 2010 1695 1700
91. T.R. Koves, P. Li, J. An, T. Akimoto, D. Slentz, and O. Ilkayeva 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 280 2005 33588 33598 (Pubitemid 41397160)
92. L.M. Redman, K.M. Huffman, L.R. Landerman, C.F. Pieper, J.R. Bain, and M.J. Muehlbauer Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women J Clin Endocrinol Metab 96 2011 E312 E321
93. S.S. Velan, N. Said, C. Durst, S. Frisbee, J. Frisbee, and R.R. Raylman Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans Am J Physiol 295 2008 R1060 R1065
94. R.E. Gimeno, and J. Cao Thematic Review Series: Glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity J Lipid Res 49 2008 2079 2088
95. H. Park, V.K. Kaushik, S. Constant, M. Prentki, E. Przybytkowski, and N.B. Ruderman Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise J Biol Chem 277 2002 32571 32577 (Pubitemid 34984761)
96. Wurie HR, Buckett L, Zammit VA. Evidence that diacylglycerol acyltransferase-1 (DGAT-1) has dual membrane-topology in the endoplasmic reticulum of HePG2 cells. J Biol Chem; in Press, doi: 10.1074/jbc.M111.251900.
97. P.J. McFie, S.L. Banman, S. Kary, and S.J. Stone Murine diacylglycerol acyltransferase-2 (DGAT2) can catalyze triacylglycerol synthesis and promote lipid droplet formation independent of its localization to the endoplasmic reticulum J Biol Chem 286 2011 28235 28246
98. S.J. Stone, M.C. Levin, P. Zhou, J. Han, T.C. Walther, and R.V. Farese Jr The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria J Biol Chem 284 2009 5352 5361
99. S. Cases, S.J. Smith, Y.-W. Zheng, H.M. Myers, S.R. Lear, and E. Sande Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis Proc Natl Acad Sci 95 1998 13018 13023 (Pubitemid 28509516)
100. S. Cases, S.J. Stone, P. Zhou, E. Yen, B. Tow, and K.D. Lardizabal Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members J Biol Chem 276 2001 38870 38876
101. M. Li, C. Paran, N.E. Wolins, and J.F. Horowitz High muscle lipid content in obesity is not due to enhanced activation of key triglyceride esterification enzymes or to the suppression of lipolytic proteins Am J Physiol Endocrinol Metab 300 2011 E699 E707
102. S. Schenk, and J.F. Horowitz Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance J Clin Invest 117 2007 1690 1698 (Pubitemid 46871353)
103. Alsted TJ, Nybo L, Schweiger M, Fledelius C, Jacobsen P, Zimmermann R, et al. Adipose triglyceride lipase in human skeletal muscle is upregulated by exercise training. Am J Physiol Endocrinol Metab 2008:90912.2008.
104. B. Schmitt, M. Fluck, J. Decombaz, R. Kreis, C. Boesch, and M. Wittwer Transcriptional adaptations of lipid metabolism in tibialis anterior muscle of endurance-trained athletes Physiol Genomics 15 2003 148 157 (Pubitemid 38089561)
105. S.A. Newsom, S. Schenk, M. Li, A.C. Everett, and J.F. Horowitz High fatty acid availability after exercise alters the regulation of muscle lipid metabolism Metabolism 60 2010 852 859
106. L. Liu, S. Yu, R.S. Khan, G.P. Ables, K.G. Bharadwaj, and Y. Hu Diacylglycerol acyl transferase 1 deficiency decreases PPAR expression and does not lead lipotoxicity in cardiac and skeletal muscle J Lipid Res 52 2010 732 744
107. P. Dobrzyn, M. Jazurek, and A. Dobrzyn Stearoyl-CoA desaturase and insulin signaling - What is the molecular switch? Biochim Biophys Acta 1797 2010 1189 1194
108. J. Wang, L. Yu, R.E. Schmidt, C. Su, X. Huang, and K. Gould Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates Biochem Biophys Res Commun 332 2005 735 742 (Pubitemid 40745175)
109. P. Dobrzyn, A. Pyrkowska, M. Jazurek, K. Szymanski, J. Langfort, and A. Dobrzyn Endurance training-induced accumulation of muscle triglycerides is coupled to upregulation of stearoyl-CoA desaturase 1 J Appl Physiol 109 2010 1653 1661
110. A. Peter, C. Weigert, H. Staiger, F. Machicao, and F. Schick Machann Jr, et al. Individual stearoyl-CoA desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is sssociated with skeletal muscle lipid storage and insulin sensitivity in vivo Diabetes 58 2009 1757 1765
111. S. Pinnamaneni, R. Southgate, M. Febbraio, and M. Watt Stearoyl CoA desaturase 1 is elevated in obesity but protects against fatty acid-induced skeletal muscle insulin resistance in vitro Diabetologia 49 2006 3027 3037 (Pubitemid 44730307)
112. M.W. Hulver, J.R. Berggren, M.J. Carper, M. Miyazaki, J.M. Ntambi, and E.P. Hoffman Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans Cell Metab 2 2005 251 261
113. R. Zimmermann, J.G. Strauss, G. Haemmerle, G. Schoiswohl, R. Birner-Gruenberger, and M. Riederer Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase Science 306 2004 1383 1386 (Pubitemid 39532517)
114. G. Fredrikson, and P. Belfrage Positional specificity of hormone-sensitive lipase from rat adipose tissue J Biol Chem 258 1983 14253 14256 (Pubitemid 14217944)
115. G. Haemmerle, R. Zimmermann, M. Hayn, C. Theussl, G. Waeg, and E. Wagner Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis J Biol Chem 277 2002 4806 4815 (Pubitemid 34968514)
116. E. Blaak, S. Schiffelers, W. Saris, M. Mensink, and M. Kooi Impaired β-adrenergically mediated lipolysis in skeletal muscle of obese subjects Diabetologia 47 2004 1462 1468 (Pubitemid 39232433)
117. P.M. Badin, K. Louche, A. Mairal, G. Liebisch, G. Schmitz, and A.C. Rustan Altered skeletal muscle lipase expression and activity contribute to insulin resistance in humans Diabetes 60 2011 1734 1742
118. J.G. Granneman, H.-P.H. Moore, R. Krishnamoorthy, and M. Rathod Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl) J Biol Chem 284 2009 34538 34544
119. J.G. Granneman, H.-P.H. Moore, E.P. Mottillo, Z. Zhu, and L. Zhou Interactions of perilipin-5 (PLIN5) with adipose trigylceride lipase (ATGL) J Biol Chem 286 2011 5126 5135
120. J.G. Granneman, H.P. Moore, E.P. Mottillo, and Z. Zhu Functional interactions between MLDP (LSDP5) and ABHD5 in the control of intracellular lipid accumulation J Biol Chem 284 2009 3049 3057
121. H. Wang, M. Bell, U. Sreenevasan, H. Hu, J. Liu, and K. Dalen Unique regulation of adipose triglyceride lipase (ATGL) by perilipin 5, a lipid droplet-associated protein J Biol Chem 286 2011 15707 15715
122. L.J.C. Van Loon Use of intramuscular triacylglycerol as a substrate source during exercise in humans J Appl Physiol 97 2004 1170 1187 (Pubitemid 39302659)
123. T. Stellingwerff, H. Boon, R.A.M. Jonkers, J.M. Senden, L.L. Spriet, and R. Koopman Significant intramyocellular lipid use during prolonged cycling in endurance-trained males as assessed by three different methodologies Am J Physiol Endocrinol Metab 292 2007 E1715 E1723
124. E. Standl, N. Lotz, T. Dexel, H. Janka, and H. Kolb Muscle triglycerides in diabetic subjects Diabetologia 18 1980 463 469
125. L.J.C. Van Loon, and B. Goodpaster Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state Pflügers Arch 451 2006 606 616 (Pubitemid 43042172)
126. R. Bassel-Duby, and E.N. Olson Signaling pathways in skeletal muscle remodeling Annu Rev Biochem 75 2006 19 37 (Pubitemid 44118024)
127. S. Lillioja, A.A. Young, C.L. Culter, J.L. Ivy, W.G. Abbott, and J.K. Zawadzki Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man J Clin Invest 80 1987 415 424
128. M. Beller, K. Thiel, P.J. Thul, and H. Jäckle Lipid droplets: A dynamic organelle moves into focus FEBS Lett 584 2010 2176 2182
129. R.V. Farese, and T.C. Walther Lipid droplets finally get a little R-E-S-P-E-C-T Cell 139 2009 855 860
130. C. Thiele, and J. Spandl Cell biology of lipid droplets Curr Opin Cell Biol 20 2008 378 385
131. T.C. Walther, and R.V. Farese Jr The life of lipid droplets Biochim Biophys Acta 1791 2009 459 466
132. R.P. DiAugustine, J.M. Schaefer, and J.R. Fouts Hepatic lipid droplets. Isolation, morphology and composition Biochem J 132 1973 323 327
133. R. Minnaard, P. Schrauwen, G. Schaart, J.A. Jorgensen, E. Lenaers, and M. Mensink Adipocyte differentiation-related protein and OXPAT in rat and human skeletal muscle: involvement in lipid accumulation and type 2 diabetes mellitus J Clin Endocrinol Metab 94 2009 4077 4085
134. S.A. Phillips, C.C. Choe, T.P. Ciaraldi, A.S. Greenberg, A.P. Kong, and S.C. Baxi Adipocyte differentiation-related protein in human skeletal muscle: relationship to insulin sensitivity Obes Res 13 2005 1321 1329
135. C. Prats, M. Donsmark, K. Qvortrup, C. Londos, C. Sztalryd, and C. Holm Decrease in intramuscular lipid droplets and translocation of HSL in response to muscle contraction and epinephrine J Lipid Res 47 2006 2392 2399 (Pubitemid 44936101)
136. N.E. Wolins, J.R. Skinner, M.J. Schoenfish, A. Tzekov, K.G. Bensch, and P.E. Bickel Adipocyte protein S3-12 coats nascent lipid droplets J Biol Chem 278 2003 37713 37721 (Pubitemid 37175296)
137. K.T. Dalen, T. Dahl, E. Holter, B. Arntsen, C. Londos, and C. Sztalryd LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues Biochim Biophys Acta 1771 2007 210 227 (Pubitemid 46210188)
138. N.E. Wolins, B.K. Quaynor, J.R. Skinner, A. Tzekov, M.A. Croce, and M.C. Gropler OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization Diabetes 55 2006 3418 3428 (Pubitemid 44923601)
139. T. Yamaguchi, S. Matsushita, K. Motojima, F. Hirose, and T. Osumi MLDP, a novel PAT family protein localized to lipid droplets and enriched in the heart, is regulated by peroxisome proliferator-activated receptor alpha J Biol Chem 281 2006 14232 14240 (Pubitemid 43848351)
140. M. Bell, H. Wang, H. Chen, J.C. McLenithan, D.W. Gong, and R.Z. Yang Consequences of lipid droplet coat protein downregulation in liver cells: abnormal lipid droplet metabolism and induction of insulin resistance Diabetes 57 2008 2037 2045
141. H. Miyoshi, S.C. Souza, M. Endo, T. Sawada, J.W. Perfield II, and C. Shimizu Perilipin overexpression in mice protects against diet-induced obesity J Lipid Res 51 2009 975 982
142. Wang H, Sreenevasan U, Hu H, Saladino A, Polster BM, Lund LM, et al. Perilipin 5, lipid droplet associated protein provides physical and metabolic linkage to mitochondria. J Lipid Res; in Press, doi: 10.1194/jlr.M017939.
143. Bosma M, Minnaard R, Sparks LM, Schaart G, Losen M, De Baets MH, et al. The lipid droplet coat protein perilipin 5 also localizes to muscle mitochondria. Histochem Cell Biol; in press, doi:10.1007/s00418-011-0888-x.
144. B.H.-J. Chang, L. Li, P. Saha, and L. Chan Absence of adipose differentiation related protein upregulates hepatic VLDL secretion, relieves hepatosteatosis and improves whole body insulin resistance in leptin-deficient mice J Lipid Res 51 2010 2132 2142
145. Y. Imai, G.M. Varela, M.B. Jackson, M.J. Graham, R.M. Crooke, and R.S. Ahima Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide Gastroenterology 132 2007 1947 1954 (Pubitemid 46677941)
146. G.M. Varela, D.A. Antwi, R. Dhir, X. Yin, N.S. Singhal, and M.J. Graham Inhibition of ADRP prevents diet-induced insulin resistance Am J Physiol Gastrointest Liver Physiol 295 2008 G621 G628
147. D. Corella, L. Qi, E.S. Tai, M. Deurenberg-Yap, C.E. Tan, and S.K. Chew Perilipin gene variation determines higher susceptibility to insulin resistance in Asian women when consuming a high-saturated fat, low-carbohydrate diet Diabetes Care 29 2006 1313 1319 (Pubitemid 44125928)
148. Y. Jang, O.Y. Kim, J.H. Lee, S.J. Koh, J.S. Chae, and J.Y. Kim Genetic variation at the perilipin locus is associated with changes in serum free fatty acids and abdominal fat following mild weight loss Int J Obes 30 2006 1601 1608 (Pubitemid 44657833)
149. L. Qi, D. Corella, J.V. Sorlí, O. Portolés, H. Shen, and O. Coltell Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women Clin Genet 66 2004 299 310 (Pubitemid 39317631)
150. R. Davoli, G. Gandolfi, S. Braglia, M. Comella, P. Zambonelli, and L. Buttazzoni New SNP of the porcine Perilipin 2 (PLIN2) gene, association with carcass traits and expression analysis in skeletal muscle Mol Biol Rep 38 2011 1575 1583
151. K. Matsusue, T. Kusakabe, T. Noguchi, S. Takiguchi, T. Suzuki, and S. Yamano Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27 Cell Metab 7 2008 302 311 (Pubitemid 351455219)
152. V. Puri, S. Konda, S. Ranjit, M. Aouadi, A. Chawla, and M. Chouinard Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage J Biol Chem 282 2007 34213 34218 (Pubitemid 350159455)
153. Wang ZQ, Yu Y, Zhang XH, Floyd EZ, Cefalu WT. Human adenovirus 36 decreases fatty acid oxidation and increases de novo lipogenesis in primary cultured human skeletal muscle cells by promoting Cidec/FSP27 expression. Int J Obes 2010.
154. D.A. Gross, E.L. Snapp, and D.L. Silver Structural insights into triglyceride storage mediated by fat storage-inducing transmembrane (FIT) protein 2 PLoS ONE 5 2010 e10796
155. B. Kadereit, P. Kumar, W.-J. Wang, D. Miranda, E.L. Snapp, and N. Severina Evolutionarily conserved gene family important for fat storage Proc Natl Acad Sci 105 2008 94 99
156. P. Bostrom, L. Andersson, M. Rutberg, J. Perman, U. Lidberg, and B.R. Johansson SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity Nat Cell Biol 9 2007 1286 1293 (Pubitemid 350042360)
157. S. Jägerström, S. Polesie, Y. Wickström, B.R. Johansson, H.D. Schröder, and K. Højlund Lipid droplets interact with mitochondria using SNAP23 Cell Biol Int 33 2009 934 940
158. I.R. Schlaepfer, L.K. Pulawa, L.D.M.C.B. Ferreira, D.E. James, W.H. Capell, and R.H. Eckel Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance J Lipid Res 44 2003 1174 1181 (Pubitemid 37279635)
159. T.H. Sollner Lipid droplets highjack SNAREs Nat Cell Biol 9 2007 1219 1220 (Pubitemid 350042349)
160. P. Boström, L. Andersson, L. Li, R. Perkins, K. Højlund, and J. Borén The assembly of lipid droplets and its relation to cellular insulin sensitivity Biochem Soc Trans 037 2009 981 985
161. P. Boström, L. Andersson, B. Vind, L. Hversen, M. Rutberg, and Y. Wickström The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes Diabetes 59 2010 1870 1878
162. N.A. Ducharme, and P.E. Bickel Lipid droplets in lipogenesis and lipolysis Endocrinology 149 2008 942 949
163. Olofsson SO, Andersson L, Hversen L, Olsson C, Myhre S, Rutberg M, et al. The formation of lipid droplets: possible role in the development of insulin resistance/type 2 diabetes. Prostaglandins Leukot Essent Fatty Acids 2011; in Press, doi: 10.1016/j.plefa.2011.04.019.
164. J. He, B.H. Goodpaster, and D.E. Kelley Effects of weight loss and physical activity on muscle lipid content and droplet size Obesity 12 2004 761 769 (Pubitemid 41127311)
165. J.C. Molero, S. Lee, I. Leizerman, A. Chajut, A. Cooper, and K. Walder Effects of rosiglitazone on intramyocellular lipid accumulation in Psammomys obesus Biochim Biophys Acta 1802 2010 235 239
166. M. Fraenkel, R. Weiss, I. Leizerman, D. Anaby, E. Golomb, and G. Leibowitz Scanning electron microscopic analysis of intramyocellular lipid droplets in an animal model of type 2 diabetes Obesity 16 2008 695 699 (Pubitemid 351328022)
167. M.A. Tarnopolsky, C.D. Rennie, H.A. Robertshaw, S.N. Fedak-Tarnopolsky, M.C. Devries, and M.J. Hamadeh Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity Am J Physiol Regul Integr Comp Physiol 292 2007 R1271 R1278
168. P. Malenfant, D.R. Joanisse, R. Theriault, B.H. Goodpaster, D.E. Kelley, and J.A. Simoneau Fat content in individual muscle fibers of lean and obese subjects Int J Obes Relat Metab Disord 25 2001 1316 1321 (Pubitemid 32835448)
169. J. Nielsen, M. Mogensen, B.F. Vind, and K. Sahlin HÃ̧jlund K, SchrÃ̧der HD, et al. Increased subsarcolemmal lipids in type 2 diabetes: effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle Am J Physiol Endocrinol Metab 298 2009 E706 E713
170. H. Hoppeler, P. Luthi, H. Claassen, E.R. Weibel, and H. Howald The ultrastructure of the normal human skeletal muscle. A morphometric analysis on untrained men, women and well-trained orienteers Pflugers Arch 344 1973 217 232
171. C.R. Taylor, E.R. Weibel, J.M. Weber, R. Vock, H. Hoppeler, and T.J. Roberts Design of the oxygen and substrate pathways. I. Model and strategy to test symmorphosis in a network structure J Exp Biol 199 1996 1643 1649 (Pubitemid 26310699)
172. R. Vock, H. Hoppeler, H. Claassen, D.X. Wu, R. Billeter, and J.M. Weber Design of the oxygen and substrate pathways. VI. structural basis of intracellular substrate supply to mitochondria in muscle cells J Exp Biol 199 1996 1689 1697 (Pubitemid 26310704)