Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: A causal mechanism or an innocent bystander?

European Journal of Endocrinology

Volumn 176, Issue 2, 2017, Pages R67-R78

  Brøns, Charlotte ^a   Grunnet, Louise Groth ^a  

^a Rigshospitalet   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

LIPID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; CERAMIDE; DIACYLGLYCEROL;

ADIPOSE TISSUE; CLINICAL TRIAL; HUMAN; INSULIN RESISTANCE; LIPID STORAGE; LIPOTOXICITY; LIVER; MITOCHONDRION; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; REVIEW; SKELETAL MUSCLE; ENDOCRINOLOGY; LIPID METABOLISM; METABOLISM; PHYSIOLOGY;

ADIPOSE TISSUE; CERAMIDES; DIABETES MELLITUS, TYPE 2; DIGLYCERIDES; ENDOCRINOLOGY; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; MUSCLE, SKELETAL;

EID: 85012008985     PISSN: 08044643     EISSN: 1479683X     Source Type: Journal    
DOI: 10.1530/EJE-16-0488     Document Type: Review

References (101)

1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014 384 766-781. (doi:10.1016/S0140-6736(14)60460-8)
2. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS & Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003 289 76-79. (doi:10.1001/jama.289.1.76)
3. Bogardus C, Lillioja S, Mott DM, Hollenbeck C & Reaven G. Relationship between degree of obesity and in vivo insulin action in man. American Journal of Physiology 1985 248 E286-E291.
4. Clausen JO, Borch-Johnsen K, Ibsen H, Bergman RN, Hougaard P, Winther K & Pedersen O. Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors. Journal of Clinical Investigation 1996 98 1195-1209. (doi:10.1172/JCI118903)
5. Romacho T, Elsen M, Rohrborn D & Eckel J. Adipose tissue and its role in organ crosstalk. Acta Physiologica 2014 210 733-753. (doi:10.1111/apha.12246)
6. Arner P & Ryden M. Fatty acids, obesity and insulin resistance. Obesity Facts 2015 8 147-155. (doi:10.1159/000381224)
7. Karpe F, Dickmann JR & Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 2011 60 2441-2449. (doi:10.2337/db11-0425)
8. Randle PJ, Garland PB, Hales CN & Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963 1 785-789. (doi:10.1016/S0140-6736(63)91500-9)
9. Hoeks J, Mensink M, Hesselink MK, Ekroos K & Schrauwen P. Long-and medium-chain fatty acids induce insulin resistance to a similar extent in humans despite marked differences in muscle fat accumulation. Journal of Clinical Endocrinology and Metabolism 2012 97 208-216. (doi:10.1210/jc.2011-1884)
10. de Ferranti S & Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clinical Chemistry 2008 54 945-955. (doi:10.1373/clinchem.2007.100156)
11. Lafontan M. Adipose tissue and adipocyte dysregulation. Diabetes and Metabolism 2014 40 16-28. (doi:10.1016/j.diabet.2013.08.002)
12. Moreno-Indias I & Tinahones FJ. Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders. Journal of Diabetes Research 2015 2015 970375. (doi:10.1155/2015/970375)
13. Tang QQ & Lane MD. Adipogenesis: from stem cell to adipocyte. Annual Review of Biochemistry 2012 81 715-736. (doi:10.1146/annurev-biochem-052110-115718)
14. Medina-Gomez G, Gray S & Vidal-Puig A. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutrition 2007 10 1132-1137. (doi:10.1017/s1368980007000614)
15. Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerx J & Ferré P. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997 46 1393-1399. (doi:10.2337/diabetes.46.9.1393)
16. Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia 2002 45 1201-1210. (doi:10.1007/s00125-002-0873-y)
17. Danforth E Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nature Genetics 2000 26 13.
18. Acosta JR, Douagi I, Andersson DP, Bäckdahl J, Rydén M, Arner P & Laurencikiene J. Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. Diabetologia 2016 59 560-570. (doi:10.1007/s00125-015-3810-6)
19. Weyer C, Foley JE, Bogardus C, Tataranni PA & Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 2000 43 1498-1506. (doi:10.1007/s001250051560)
20. Eriksson JW, Smith U, Waagstein F, Wysocki M & Jansson PA. Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon? Diabetes 1999 48 1572-1578. (doi:10.2337/diabetes.48.8.1572)
21. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T et al. Dynamics of fat cell turnover in humans. Nature 2008 453 783-787. (doi:10.1038/nature06902)
22. Fang L, Guo F, Zhou L, Stahl R & Grams J. The cell size and distribution of adipocytes from subcutaneous and visceral fat is associated with type 2 diabetes mellitus in humans. Adipocyte 2015 4 273-279. (doi:10.1080/21623945.2015.1034920)
23. Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T & Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and 'hyperleptinaemia'. Diabetologia 2007 50 625-633. (doi:10.1007/s00125-006-0572-1)
24. Yang J, Eliasson B, Smith U, Cushman SW & Sherman AS. The size of large adipose cells is a predictor of insulin resistance in firstdegree relatives of type 2 diabetic patients. Obesity 2012 20 932-938. (doi:10.1038/oby.2011.371)
25. Pasarica M, Xie H, Hymel D, Bray G, Greenway F, Ravussin E & Smith SR. Lower total adipocyte number but no evidence for small adipocyte depletion in patients with type 2 diabetes. Diabetes Care 2009 32 900-902. (doi:10.2337/dc08-2240)
26. Reitman ML, Mason MM, Moitra J, Gavrilova O, Marcus-Samuels B, Eckhaus M & Vinson C. Transgenic mice lacking white fat: models for understanding human lipoatrophic diabetes. Annals of the New York Academy of Sciences 1999 892 289-296. (doi:10.1111/j.1749-6632.1999.tb07802.x)
27. Garg A. Clinical review#: lipodystrophies: genetic and acquired body fat disorders. Journal of Clinical Endocrinology and Metabolism 2011 96 3313-3325. (doi:10.1210/jc.2011-1159)
28. Kim JY, van de WE, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. Journal of Clinical Investigation 2007 117 2621-2637. (doi:10.1172/JCI31021)
29. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 2012 483 350-354. (doi:10.1038/nature10798)
30. Alligier M, Gabert L, Meugnier E, Lambert-Porcheron S, Chanseaume E, Pilleul F, Debard C, Sauvinet V, Morio B, Vidal-Puig A et al. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. Journal of Clinical Endocrinology and Metabolism 2013 98 802-810. (doi:10.1210/jc.2012-3289)
31. Pellegrinelli V, Carobbio S & Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 2016 59 1075-1088. (doi:10.1007/s00125-016-3933-4)
32. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C & Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991 303 1019-1022. (doi:10.1136/bmj.303.6809.1019)
33. Hales CN & Barker DJP. The thrifty phenotype hypothesis: type 2 diabetes. British Medical Bulletin 2001 60 5-20. (doi:10.1093/bmb/60.1.5)
34. Pilgaard K, Hammershaimb MT, Grunnet L, Eiberg H, Van Hall G, Fallentin E, Larsen T, Larsen R, Poulsen P & Vaag A. Differential nongenetic impact of birth weight vs third-trimester growth velocity on glucose metabolism and magnetic resonance imaging abdominal obesity in young healthy twins. Journal of Clinical Endocrinology and Metabolism 2011 96 2835-2843. (doi:10.1210/jc.2011-0577)
35. Rasmussen EL, Malis C, Jensen CB, Jensen JE, Storgaard H, Poulsen P, Pilgaard K, Schou JH, Madsbad S, Astrup A et al. Altered fat tissue distribution in young adult men who had low birth weight. Diabetes Care 2005 28 151-153. (doi:10.2337/diacare.28.1.151)
36. Schultz NS, Broholm C, Gillberg L, Mortensen B, Jorgensen SW, Schultz HS, Scheele C, Wojtaszewski JFP, Pedersen BK & Vaag A. Impaired leptin gene expression and release in cultured preadipocytes isolated from individuals born with low birth weight. Diabetes 2013 63 111-121. (doi:10.2337/db13-0621)
37. de Zegher F, Diaz M, Sebastiani G, Martín-Ancel A, Sánchez-Infantes D, López-Bermejo A & Ibáñez L. Abundance of circulating preadipocyte factor 1 in early life. Diabetes Care 2012 35 848-849. (doi:10.2337/dc11-1990)
38. Sebastiani G, Diaz M, Bassols J, Aragonés G, López-Bermejo A, de Zegher F & Ibáñez L. The sequence of prenatal growth restraint and post-natal catch-up growth leads to a thicker intima-media and more pre-peritoneal and hepatic fat by age 3-6 years. Pediatric Obesity 2015 11 251-257. (doi:10.1111/ijpo.12053)
39. Ferland-McCollough D, Fernandez-Twinn DS, Cannell IG, David H, Warner M, Vaag AA, Bork-Jensen J, Brøns C, Gant TW, Willis AE et al. Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death and Differentiation 2012 19 1003-1012. (doi:10.1038/cdd.2011.183)
40. Rojas-Rodriguez R, Lifshitz LM, Bellve KD, Min SY, Pires J, Leung K, Boeras C, Sert A, Draper JT, Corvera S et al. Human adipose tissue expansion in pregnancy is impaired in gestational diabetes mellitus. Diabetologia 2015 58 2106-2114. (doi:10.1007/s00125-015-3662-0)
41. Liang X, Yang Q, Fu X, Rogers CJ, Wang B, Pan H, Zhu MJ, Nathanielsz PW & Du M. Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice. Journal of Physiology 2016 594 4453-4466. (doi:10.1113/JP272123)
42. Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P, Buchholz BA, Eriksson M, Arner E, Hauner H et al. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 2011 478 110-113. (doi:10.1038/nature10426)
43. Boden G, Lebed B, Schatz M, Homko C & Lemieux S. Effects of acute changes of plasma FFA on intramuscular fat content and insulin resistance in healthy subjects. Diabetes 2001 50 1612-1617. (doi:10.2337/diabetes.50.7.1612)
44. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. Journal of Clinical Investigation 1999 103 253-259. (doi:10.1172/JCI5001)
45. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW & Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. Journal of Clinical Investigation 1996 97 2859-2865. (doi:10.1172/JCI118742)
46. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, Defronzo RA & Cusi K. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 2005 54 1640-1648. (doi:10.2337/diabetes.54.6.1640)
47. Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G & Olefsky JM. Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. Journal of Clinical Endocrinology and Metabolism 2002 87 226-234. (doi:10.1210/jcem.87.1.8187)
48. Storgaard H, Jensen CB, Bjornholm M, Song XM, Madsbad S, Zierath JR & Vaag AA. Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2004 89 1301-1311. (doi:10.1210/jc.2003-031243)
49. Tremblay F, Lavigne C, Jacques H & Marette A. Defective insulin-induced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both Akt/protein kinase B and atypical protein kinase C (zeta/lambda) activities. Diabetes 2001 50 1901-1910. (doi:10.2337/diabetes.50.8.1901)
50. Zierath JR, Houseknecht KL, Gnudi L & Kahn BB. High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. Diabetes 1997 46 215-223. (doi:10.2337/diab.46.2.215)
51. Galgani JE, Moro C & Ravussin E. Metabolic flexibility and insulin resistance. American Journal of Physiology: Endocrinology and Metabolism 2008 295 E1009-E1017. (doi:10.1152/ajpendo.90558.2008).
52. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Shulman GI & Roden M. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999 42 113-116. (doi:10.1007/s001250051123)
53. Kelley DE, Goodpaster BH & Storlien L. Muscle triglyceride and insulin resistance. Annual Review of Nutrition 2002 22 325-346. (doi:10.1146/annurev.nutr.22.010402.102912)
54. Schrauwen-Hinderling VB, van Loon LJ, Koopman R, Nicolay K, Saris WH & Kooi ME. Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle. Journal of Applied Physiology (1985) 2003 95 2328-2332. (doi:10.1152/japplphysiol.00304.2003)
55. Goodpaster BH, Theriault R, Watkins SC & Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism 2000 49 467-472. (doi:10.1016/S0026-0495(00)80010-4)
56. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD et al. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 1999 48 1113-1119. (doi:10.2337/diabetes.48.5.1113)
57. Shulman GI. Cellular mechanisms of insulin resistance. Journal of Clinical Investigation 2000 106 171-176. (doi:10.1172/JCI10583)
58. Itani SI, Ruderman NB, Schmieder F & Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002 51 2005-2011. (doi:10.2337/diabetes.51.7.2005)
59. Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. Journal of Biological Chemistry 2002 277 50230-50236. (doi:10.1074/jbc.M200958200)
60. Straczkowski M, Kowalska I, Nikolajuk A, Dzienis-Straczkowska S, Kinalska I, Baranowski M, Zendzian-Piotrowska M, Brzezinska Z & Gorski J. Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. Diabetes 2004 53 1215-1221. (doi:10.2337/diabetes.53.5.1215)
61. Straczkowski M, Kowalska I, Baranowski M, Nikolajuk A, Otziomek E, Zabielski P, Adamska A, Blachnio A, Gorski J & Gorska M. Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes. Diabetologia 2007 50 2366-2373. (doi:10.1007/s00125-007-0781-2)
62. Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, Jelenik T, Muller J, Herder C, Nowotny P et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. PNAS 2014 111 9597-9602. (doi:10.1073/pnas.1409229111)
63. Bergman BC, Hunerdosse DM, Kerege A, Playdon MC & Perreault L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia 2012 55 1140-1150. (doi:10.1007/s00125-011-2419-7)
64. Ritter O, Jelenik T & Roden M. Lipid-mediated muscle insulin resistance: different fat, different pathways? Journal of Molecular Medicine 2015 93 831-843. (doi:10.1007/s00109-015-1310-2)
65. Nowotny B, Zahiragic L, Krog D, Nowotny PJ, Herder C, Carstensen M, Yoshimura T, Szendroedi J, Phielix E, Schadewaldt P et al. Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. Diabetes 2013 62 2240-2248. (doi:10.2337/db12-1179)
66. Coen PM, Hames KC, Leachman EM, DeLany JP, Ritov VB, Menshikova EV, Dubé JJ, Stefanovic-Racic M, Toledo FGS & Goodpaster BH. Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity. Obesity 2013 21 2362-2371. (doi:10.1002/oby.20381)
67. Goodpaster BH, He J, Watkins S & Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurancetrained athletes. Journal of Clinical Endocrinology and Metabolism 2001 86 5755-5761. (doi:10.1210/jcem.86.12.8075)
68. Muoio DM. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochimica et Biophysica Acta 2010 1801 281-288. (doi:10.1016/j.bbalip.2009.11.007)
69. Schenk S & Horowitz JF. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. Journal of Clinical Investigation 2007 117 1690-1698. (doi:10.1172/JCI30566)
70. Gemmink A, Bosma M, Kuijpers HJ, Hoeks J, Schaart G, van Zandvoort MA, Schrauwen P & Hesselink MK. Decoration of intramyocellular lipid droplets with PLIN5 modulates fastinginduced insulin resistance and lipotoxicity in humans. Diabetologia 2016 59 1040-1048. (doi:10.1007/s00125-016-3865-z)
71. Guo Z, Burguera B & Jensen MD. Kinetics of intramuscular triglyceride fatty acids in exercising humans. Journal of Applied Physiology (1985) 2000 89 2057-2064.
72. Bucher J, Krusi M, Zueger T, Ith M, Stettler C, Diem P, Boesch C, Kreis R & Christ E. The effect of a single 2 h bout of aerobic exercise on ectopic lipids in skeletal muscle, liver and the myocardium. Diabetologia 2014 57 1001-1005. (doi:10.1007/s00125-014-3193-0)
73. Dubé JJ, Amati F, Stefanovic-Racic M, Toledo FG, Sauers SE & Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. American Journal of Physiology: Endocrinology and Metabolism 2008 294 E882-E888. (doi:10.1152/ajpendo.00769.2007)
74. Ahmed M. Non-alcoholic fatty liver disease in 2015. World Journal of Hepatology 2015 7 1450-1459. (doi:10.4254/wjh.v7.i11.1450)
75. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012 142 711-725. (doi:10.1053/j.gastro.2012.02.003)
76. Levene AP & Goldin RD. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology 2012 61 141-152. (doi:10.1111/j.1365-2559.2011.04145.x)
77. Grunnet LG, Laurila E, Hansson O, Almgren P, Groop L, Brøns C, Poulsen P & Vaag A. The triglyceride content in skeletal muscle is associated with hepatic but not peripheral insulin resistance in elderly twins. Journal of Clinical Endocrinology and Metabolism 2012 97 4571-4577. (doi:10.1210/jc.2012-2061)
78. van Herpen NA, Schrauwen-Hinderling VB, Schaart G, Mensink RP & Schrauwen P. Three weeks on a high-fat diet increases intrahepatic lipid accumulation and decreases metabolic flexibility in healthy overweight men. Journal of Clinical Endocrinology and Metabolism 2011 96 E691-E695. (doi:10.1210/jc.2010-2243)
79. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006 312 734-737. (doi:10.1126/science.1123965)
80. Dufour S & Petersen KF. Disassociation of liver and muscle insulin resistance from ectopic lipid accumulation in low-birth-weight individuals. Journal of Clinical Endocrinology and Metabolism 2011 96 3873-3880. (doi:10.1210/jc.2011-1747)
81. Brøns C, Jacobsen S, Hiscock N, White A, Nilsson E, Dunger D, Astrup A, Quistorff B & Vaag A. Effects of high-fat overfeeding on mitochondrial function, glucose and fat metabolism, and adipokine levels in low-birth-weight subjects. American Journal of Physiology: Endocrinology and Metabolism 2012 302 E43-E51. (doi:10.1152/ajpendo.00095.2011)
82. Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL & Shulman GI. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007 56 1376-1381. (doi:10.2337/db06-0783)
83. Petersen KF, Sylvie D & Gerald IS. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Medicine 2005 2 e233. (doi:10.1371/journal.pmed.0020233)
84. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW & Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003 300 1140-1142. (doi:10.1126/science.1082889)
85. Morino K, Petersen KF & Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006 55 (Supplement 2) S9-S15. (doi:10.2337/db06-S002)
86. Garcia-Roves P, Huss JM, Han DH, Hancock CR, Iglesias-Gutierrez E, Chen M & Holloszy JO. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. PNAS 2007 104 10709-10713. (doi:10.1073/pnas.0704024104)
87. Stephenson EJ, Camera DM, Jenkins TA, Kosari S, Lee JS, Hawley JA & Stepto NK. Skeletal muscle respiratory capacity is enhanced in rats consuming an obesogenic Western diet. American Journal of Physiology: Endocrinology and Metabolism 2012 302 E1541-E1549. (doi:10.1152/ajpendo.00590.2011)
88. James AM & Murphy MP. How mitochondrial damage affects cell function. Journal of Biomedical Science 2002 9 475-487. (doi:10.1007/BF02254975)
89. Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA & Smith SR. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005 54 1926-1933. (doi:10.2337/diabetes.54.7.1926)
90. Chanseaume E, Malpuech-Brugere C, Patrac V, Bielicki G, Rousset P, Couturier K, Salles J, Renou JP, Boirie Y & Morio B. Diets high in sugar, fat, and energy induce muscle type-specific adaptations in mitochondrial functions in rats. Journal of Nutrition 2006 136 2194-2200.
91. Puigserver P, Wu Z, Park CW, Graves R, Wright M & Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998 92 829-839. (doi:10.1016/S0092-8674(00)81410-5)
92. Larrouy D, Vidal H, Andreelli F, Laville M & Langin D. Cloning and mRNA tissue distribution of human PPARgamma coactivator-1. International Journal of Obesity and Related Metabolic Disorders 1999 23 1327-1332. (doi:10.1038/sj.ijo.0801106)
93. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP & Mandarino LJ. Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. Journal of Biological Chemistry 2005 280 10290-10297. (doi:10.1074/jbc.M408985200)
94. Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhausl W & Roden M. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 2006 55 136-140. (doi:10.2337/diabetes.55.01.06.db05-1286)
95. Brøns C, Jensen CB, Storgaard H, Hiscock NJ, White A, Appel JS, Jacobsen S, Nilsson E, Larsen CM, Astrup A et al. Impact of shortterm high-fat feeding on glucose and insulin metabolism in young healthy men. Journal of Physiology 2009 587 2387-2397. (doi:10.1113/jphysiol.2009.169078)
96. Hoeks J, Hesselink M, Russell A, Mensink M, Saris WH, Mensink RP & Schrauwen P. Peroxisome proliferator-activated receptor-gamma coactivator-1 and insulin resistance: acute effect of fatty acids. Diabetologia 2006 49 2419-2426. (doi:10.1007/s00125-006-0369-2)
97. Ling C, Poulsen P, Carlsson E, Ridderstrile M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L & Vaag A. Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. Journal of Clinical Investigation 2004 114 1518-1526. (doi:10.1172/JCI21889)
98. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 2003 34 267-273. (doi:10.1038/ng1180)
99. Brøns C, Jacobsen S, Nilsson E, Rönn T, Jensen CB, Storgaard H, Poulsen P, Groop L, Ling C, Astrup A & Vaag A. Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weightdependent manner. Journal of Clinical Endocrinology & Metabolism 2010 95 3048-3056. (doi:10.1210/jc.2009-2413)
100. Vettor R, Milan G, Franzin C, Sanna M, De Coppi P, Rizzuto R & Federspil G. The origin of intermuscular adipose tissue and its pathophysiological implications. American Journal of Physiology: Endocrinology and Metabolism 2009 297 E987-E998. (doi:10.1152/ajpendo.00229.2009)
101. Boettcher M, Machann J, Stefan N, Thamer C, Häring HU, Claussen CD, Fritsche A & Schick F. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. Journal of Magnetic Resonance Imaging 2009 29 1340-1345. (doi:10.1002/jmri.21754)