Lipid oversupply, selective insulin resistance, and lipotoxicity: Molecular mechanisms

Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

Volumn 1801, Issue 3, 2010, Pages 252-265

  Chavez, Jose Antonio ^a   Summers, Scott A ^a,b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b DUKE NUS MEDICAL SCHOOL   (Singapore)

Author keywords

Diabetes; Genetic manipulation; Insulin resistance; Lipid; Lipid metabolism; Lipotoxicity; Metabolic syndrome; Metabolism; Sphingolipids

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACETYL COENZYME A CARBOXYLASE; CERAMIDE GLUCOSYLTRANSFERASE; DIACYLGLYCEROL ACYLTRANSFERASE; FATTY ACID; FATTY ACID SYNTHASE; GLYCEROL PHOSPHATE ACYL TRANSFERASE; GLYCEROLIPID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LIPID; LYSOPHOSPHATIDATE ACYLTRANSFERASES; METFORMIN; PHOSPHATIDATE PHOSPHATASE; SERINE PALMITOYLTRANSFERASE; SPHINGOLIPID; UNCLASSIFIED DRUG;

GENOMICS; INSULIN RESISTANCE; LIPID METABOLISM; LIPID OXIDATION; LIPID STORAGE; LIPID TRANSPORT; LIPIDOMICS; LIPIDOSIS; LIPOGENESIS; LIPOTOXICITY; MOLECULAR DYNAMICS; PRIORITY JOURNAL; REVIEW;

ANIMALS; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; LIPID PEROXIDATION; METABOLIC DISEASES; METABOLIC NETWORKS AND PATHWAYS; MODELS, BIOLOGICAL; SPHINGOLIPIDS; TRIGLYCERIDES;

EID: 76049095119     PISSN: 13881981     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbalip.2009.09.015     Document Type: Review

References (190)

1. McGarry J.D. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51 (2002) 7-18
2. CDC. U.S. Center for Disease Control-National Diabetes Fact Sheet, vol. 2009 (2009)
3. CDC. U.S. Center for Disease Control-Obesity Trends, vol. 2009 (2009)
4. Low S., Chin M.C., and Deurenberg-Yap M. Review on epidemic of obesity. Ann. Acad. Med. Singapore 38 (2009) 57-59
5. WHO. World Health Organization - Diabetes Programme, vol. 2009 (2009)
6. WHO. World Health Organization - Cardiovascular Disease Programme, vol. 2009 (2009)
7. Brown M.S., and Goldstein J.L. Selective versus total insulin resistance: a pathogenic paradox. Cell. Metab. 7 (2008) 95-96
8. Kim J.K., Fillmore J.J., Chen Y., Yu C., Moore I.K., Pypaert M., Lutz E.P., Kako Y., Velez-Carrasco W., Goldberg I.J., Breslow J.L., and Shulman G.I. Tissue-specific overexpression of lipoprotein lipase causes tissue- specific insulin resistance. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 7522-7527
9. Ferreira L.D., Pulawa L.K., Jensen D.R., and Eckel R.H. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes 50 (2001) 1064-1068
10. Listenberger L.L., and Schaffer J.E. Mechanisms of lipoapoptosis: implications for human heart disease. Trends. Cardiovasc. Med. 12 (2002) 134-138
11. Borradaile N.M., and Schaffer J.E. Lipotoxicity in the heart. Curr. Hypertens. Rep. 7 (2005) 412-417
12. Schaffer J.E. Lipotoxicity: when tissues overeat. Curr. Opin. Lipidol. 14 (2003) 281-287
13. Chiu H.C., Kovacs A., Ford D.A., Hsu F.F., Garcia R., Herrero P., Saffitz J.E., and Schaffer J.E. A novel mouse model of lipotoxic cardiomyopathy. J. Clin. Invest. 107 (2001) 813-822
14. Park T.S., Hu Y., Noh H.L., Drosatos K., Okajima K., Buchanan J., Tuinei J., Homma S., Jiang X.C., Abel E.D., and Goldberg I.J. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J. Lipid. Res. 49 (2008) 2101-2112
15. Pappan K.L., Pan Z., Kwon G., Marshall C.A., Coleman T., Goldberg I.J., McDaniel M.L., and Semenkovich C.F. Pancreatic beta-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion. J. Biol. Chem. 280 (2005) 9023-9029
16. Unger R.H. Lipotoxic diseases. Annu. Rev. Med. 53 (2002) 319-336
17. Unger R.H. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144 (2003) 5159-5165
18. Unger R.H., and Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int. J. Obes. Relat. Metab. Disord. 24 Suppl. 4 (2000) S28-32
19. Unger R.H., and Zhou Y.T. Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50 Suppl. 1 (2001) S118-121
20. Prentki M., and Madiraju S.R. Glycerolipid metabolism and signaling in health and disease. Endocr. Rev. 29 (2008) 647-676
21. Coleman R.A., and Lee D.P. Enzymes of triacylglycerol synthesis and their regulation. Prog. Lipid. Res. 43 (2004) 134-176
22. Kennedy E.P. Biosynthesis of complex lipids. Fed. Proc. 20 (1961) 934-940
23. Wendel A.A., Lewin T.M., and Coleman R.A. Glycerol-3-phosphate acyltransferases: Rate limiting enzymes of triacylglycerol biosynthesis. Biochim. Biophys. Acta 179 6 (2008) 501-506
24. Gimeno R.E., and Cao J. Thematic review series: glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity. J. Lipid. Res. 49 (2008) 2079-2088
25. Hammond L.E., Gallagher P.A., Wang S., Hiller S., Kluckman K.D., Posey-Marcos E.L., Maeda N., and Coleman R.A. Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol. Cell. Biol. 22 (2002) 8204-8214
26. Neschen S., Morino K., Hammond L.E., Zhang D., Liu Z.X., Romanelli A.J., Cline G.W., Pongratz R.L., Zhang X.M., Choi C.S., Coleman R.A., and Shulman G.I. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice. Cell. Metab. 2 (2005) 55-65
27. Yazdi M., Ahnmark A., William-Olsson L., Snaith M., Turner N., Osla F., Wedin M., Asztely A.K., Elmgren A., Bohlooly Y.M., Schreyer S., and Linden D. The role of mitochondrial glycerol-3-phosphate acyltransferase-1 in regulating lipid and glucose homeostasis in high-fat diet fed mice. Biochem. Biophys. Res. Commun. 369 (2008) 1065-1070
28. Xu H., Wilcox D., Nguyen P., Voorbach M., Suhar T., Morgan S.J., An W.F., Ge L., Green J., Wu Z., Gimeno R.E., Reilly R., Jacobson P.B., Collins C.A., Landschulz K., and Surowy T. Hepatic knockdown of mitochondrial GPAT1 in ob/ob mice improves metabolic profile. Biochem. Biophys. Res. Commun. 349 (2006) 439-448
29. Nagle C.A., An J., Shiota M., Torres T.P., Cline G.W., Liu Z.X., Wang S., Catlin R.L., Shulman G.I., Newgard C.B., and Coleman R.A. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance. J. Biol. Chem. 282 (2007) 14807-14815
30. Takeuchi K., and Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am. J. Physiol. Endocrinol. Metab. 296 (2009) E1195-E1209
31. Agarwal A.K., Arioglu E., De Almeida S., Akkoc N., Taylor S.I., Bowcock A.M., Barnes R.I., and Garg A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat. Genet. 31 (2002) 21-23
32. Agarwal A.K., Simha V., Oral E.A., Moran S.A., Gorden P., O'Rahilly S., Zaidi Z., Gurakan F., Arslanian S.A., Klar A., Ricker A., White N.H., Bindl L., Herbst K., Kennel K., Patel S.B., Al-Gazali L., and Garg A. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J. Clin. Endocrinol. Metab. 88 (2003) 4840-4847
33. Agarwal A.K., and Garg A. Genetic basis of lipodystrophies and management of metabolic complications. Annu. Rev. Med. 57 (2006) 297-311
34. Agarwal A.K., and Garg A. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends. Endocrinol. Metab. 14 (2003) 214-221
35. Agarwal A.K., Barnes R.I., and Garg A. Genetic basis of congenital generalized lipodystrophy. Int. J. Obes. Relat. Metab. Disord. 28 (2004) 336-339
36. Cortes V.A., Curtis D.E., Sukumaran S., Shao X., Parameswara V., Rashid S., Smith A.R., Ren J., Esser V., Hammer R.E., Agarwal A.K., Horton J.D., and Garg A. Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell. Metab. 9 (2009) 165-176
37. Reue K., and Brindley D.N. Thematic Review Series: glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J. Lipid. Res. 49 (2008) 2493-2503
38. Finck B.N., Gropler M.C., Chen Z., Leone T.C., Croce M.A., Harris T.E., Lawrence Jr. J.C., and Kelly D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell. Metab. 4 (2006) 199-210
39. Langner C.A., Birkenmeier E.H., Ben-Zeev O., Schotz M.C., Sweet H.O., Davisson M.T., and Gordon J.I. The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. J. Biol. Chem. 264 (1989) 7994-8003
40. Langner C.A., Birkenmeier E.H., Roth K.A., Bronson R.T., and Gordon J.I. Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J. Biol. Chem. 266 (1991) 11955-11964
41. Reue K., Xu P., Wang X.P., and Slavin B.G. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene. J. Lipid. Res. 41 (2000) 1067-1076
42. Phan J., and Reue K. Lipin, a lipodystrophy and obesity gene. Cell. Metab. 1 (2005) 73-83
43. Nagaya H., Wada I., Jia Y.J., and Kanoh H. Diacylglycerol kinase delta suppresses ER-to-Golgi traffic via its SAM and PH domains. Mol. Biol. Cell. 13 (2002) 302-316
44. Crotty T., Cai J., Sakane F., Taketomi A., Prescott S.M., and Topham M.K. Diacylglycerol kinase delta regulates protein kinase C and epidermal growth factor receptor signaling. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 15485-15490
45. Chibalin A.V., Leng Y., Vieira E., Krook A., Bjornholm M., Long Y.C., Kotova O., Zhong Z., Sakane F., Steiler T., Nylen C., Wang J., Laakso M., Topham M.K., Gilbert M., Wallberg-Henriksson H., and Zierath J.R. Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell 132 (2008) 375-386
46. Chen H.C. Enhancing energy and glucose metabolism by disrupting triglyceride synthesis: Lessons from mice lacking DGAT1. Nutr. Metab. (Lond). 3 (2006) 10
47. Smith S.J., Cases S., Jensen D.R., Chen H.C., Sande E., Tow B., Sanan D.A., Raber J., Eckel R.H., and Farese Jr. R.V. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat. Genet. 25 (2000) 87-90
48. Buhman K.K., Smith S.J., Stone S.J., Repa J.J., Wong J.S., Knapp Jr. F.F., Burri B.J., Hamilton R.L., Abumrad N.A., and Farese R.V. DGAT1 is not essential for intestinal triacylglycerol absorption or chylomicron synthesis. J. Biol. Chem. 277 (2002) 25474-25479
49. Chen H.C., Jensen D.R., Myers H.M., Eckel R.H., and Farese Jr. R.V. Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1. J. Clin. Invest. 111 (2003) 1715-1722
50. Chen H.C., Smith S.J., Ladha Z., Jensen D.R., Ferreira L.D., Pulawa L.K., McGuire J.G., Pitas R.E., Eckel R.H., and Farese R.V. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J. Clin. Invest. 109 (2002) 1049-1055
51. Streeper R.S., Koliwad S.K., Villanueva C.J., and Farese Jr. R.V. Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin. Am. J. Physiol. Endocrinol. Metab. 291 (2006) E388-394
52. Chen H.C., Stone S.J., Zhou P., Buhman K.K., and Farese R.V. Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue. Diabetes 51 (2002) 3189-3195
53. Yu X.X., Murray S.F., Pandey S.K., Booten S.L., Bao D., Song X.Z., Kelly S., Chen S., McKay R., Monia B.P., and Bhanot S. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42 (2005) 362-371
54. Choi C.S., Savage D.B., Kulkarni A., Yu X.X., Liu Z.X., Morino K., Kim S., Distefano A., Samuel V.T., Neschen S., Zhang D., Wang A., Zhang X.M., Kahn M., Cline G.W., Pandey S.K., Geisler J.G., Bhanot S., Monia B.P., and Shulman G.I. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J. Biol. Chem. 282 (2007) 22678-22688
55. Yamaguchi K., Yang L., McCall S., Huang J., Yu X.X., Pandey S.K., Bhanot S., Monia B.P., Li Y.X., and Diehl A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45 (2007) 1366-1374
56. Monetti M., Levin M.C., Watt M.J., Sajan M.P., Marmor S., Hubbard B.K., Stevens R.D., Bain J.R., Newgard C.B., Farese Sr. R.V., Hevener A.L., and Farese R.V. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell. Metab. 6 (2007) 69-78
57. Dube J.J., Amati F., Stefanovic-Racic M., Toledo F.G., Sauers S.E., and Goodpaster B.H. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. Am. J. Physiol. Endocrinol. Metab. 294 (2008) E882-888
58. Goodpaster B.H., He J., Watkins S., and Kelley D.E. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J. Clin. Endocrinol. Metab. 86 (2001) 5755-5761
59. van Loon L.J., and Goodpaster B.H. Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state. Pflugers. Arch. 451 (2006) 606-616
60. Liu L., Zhang Y., Chen N., Shi X., Tsang B., and Yu Y.H. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J. Clin. Invest. 117 (2007) 1679-1689
61. Roorda B.D., Hesselink M.K., Schaart G., Moonen-Kornips E., Martinez-Martinez P., Losen M., De Baets M.H., Mensink R.P., and Schrauwen P. DGAT1 overexpression in muscle by in vivo DNA electroporation increases intramyocellular lipid content. J. Lipid. Res. 46 (2005) 230-236
62. Levin M.C., Monetti M., Watt M.J., Sajan M.P., Stevens R.D., Bain J.R., Newgard C.B., Farese Sr. R.V., and Farese Jr. R.V. Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle. Am. J. Physiol. Endocrinol. Metab. 293 (2007) E1772-1781
63. Yen C.L., Stone S.J., Koliwad S., Harris C., and Farese R.V. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid. Res. 49 (2008) 2283-2301
64. Ntambi J.M., Miyazaki M., Stoehr J.P., Lan H., Kendziorski C.M., Yandell B.S., Song Y., Cohen P., Friedman J.M., and Attie A.D. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 11482-11486
65. Miyazaki M., Sampath H., Liu X., Flowers M.T., Chu K., Dobrzyn A., and Ntambi J.M. Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice. Biochem. Biophys. Res. Commun. 380 (2009) 818-822
66. Man W.C., Miyazaki M., Chu K., and Ntambi J. Colocalization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis. J. Lipid. Res. 47 (2006) 1928-1939
67. Gutierrez-Juarez R., Pocai A., Mulas C., Ono H., Bhanot S., Monia B.P., and Rossetti L. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J. Clin. Invest. 116 (2006) 1686-1695
68. Flowers M.T., Miyazaki M., Liu X., and Ntambi J.M. Probing the role of stearoyl-CoA desaturase-1 in hepatic insulin resistance. J. Clin. Invest. 116 (2006) 1478-1481
69. Peter A., Weigert C., Staiger H., Machicao F., Schick F., Machann J., Stefan N., Thamer C., Haring H.U., and Schleicher E. Individual stearoyl-CoA desaturase 1 (SCD1) expression modulates ER stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo. Diabetes 58 8 (2009) 1757-1765
70. Li Z.Z., Berk M., McIntyre T.M., and Feldstein A.E. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284 (2009) 5637-5644
71. Brown J.M., Chung S., Sawyer J.K., Degirolamo C., Alger H.M., Nguyen T., Zhu X., Duong M.N., Wibley A.L., Shah R., Davis M.A., Kelley K., Wilson M.D., Kent C., Parks J.S., and Rudel L.L. Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation 118 (2008) 1467-1475
72. Attie A.D., Flowers M.T., Flowers J.B., Groen A.K., Kuipers F., and Ntambi J.M. Stearoyl-CoA desaturase deficiency, hypercholesterolemia, cholestasis, and diabetes. Nutr. Rev. 65 (2007) S35-38
73. Flowers J.B., Rabaglia M.E., Schueler K.L., Flowers M.T., Lan H., Keller M.P., Ntambi J.M., and Attie A.D. Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 56 (2007) 1228-1239
74. Dobrzyn P., Dobrzyn A., Miyazaki M., Cohen P., Asilmaz E., Hardie D.G., Friedman J.M., and Ntambi J.M. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 6409-6414
75. Zechner R., Kienesberger P.C., Haemmerle G., Zimmermann R., and Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid. Res. 50 (2009) 3-21
76. Zimmermann R., Lass A., Haemmerle G., and Zechner R. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim. Biophys. Acta 1791 (2009) 494-500
77. Zimmermann R., Strauss J.G., Haemmerle G., Schoiswohl G., Birner-Gruenberger R., Riederer M., Lass A., Neuberger G., Eisenhaber F., Hermetter A., and Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306 (2004) 1383-1386
78. Harada K., Shen W.J., Patel S., Natu V., Wang J., Osuga J., Ishibashi S., and Kraemer F.B. Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. Am. J. Physiol. Endocrinol. Metab. 285 (2003) E1182-1195
79. Okazaki H., Osuga J., Tamura Y., Yahagi N., Tomita S., Shionoiri F., Iizuka Y., Ohashi K., Harada K., Kimura S., Gotoda T., Shimano H., Yamada N., and Ishibashi S. Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases. Diabetes 51 (2002) 3368-3375
80. Haemmerle G., Zimmermann R., Hayn M., Theussl C., Waeg G., Wagner E., Sattler W., Magin T.M., Wagner E.F., and Zechner R. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J. Biol. Chem. 277 (2002) 4806-4815
81. Strom K., Hansson O., Lucas S., Nevsten P., Fernandez C., Klint C., Moverare-Skrtic S., Sundler F., Ohlsson C., and Holm C. Attainment of brown adipocyte features in white adipocytes of hormone-sensitive lipase null mice. PLoS One 3 (2008) e1793
82. Cinti S., Mitchell G., Barbatelli G., Murano I., Ceresi E., Faloia E., Wang S., Fortier M., Greenberg A.S., and Obin M.S. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid. Res. 46 (2005) 2347-2355
83. Park S.Y., Kim H.J., Wang S., Higashimori T., Dong J., Kim Y.J., Cline G., Li H., Prentki M., Shulman G.I., Mitchell G.A., and Kim J.K. Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart. Am. J. Physiol. Endocrinol. Metab. 289 (2005) E30-39
84. Voshol P.J., Haemmerle G., Ouwens D.M., Zimmermann R., Zechner R., Teusink B., Maassen J.A., Havekes L.M., and Romijn J.A. Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice. Endocrinology 144 (2003) 3456-3462
85. Mulder H., Sorhede-Winzell M., Contreras J.A., Fex M., Strom K., Ploug T., Galbo H., Arner P., Lundberg C., Sundler F., Ahren B., and Holm C. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact. J. Biol. Chem. 278 (2003) 36380-36388
86. Roduit R., Masiello P., Wang S.P., Li H., Mitchell G.A., and Prentki M. A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice. Diabetes 50 (2001) 1970-1975
87. Larsson S., Wierup N., Sundler F., Eliasson L., and Holm C. Lack of cholesterol mobilization in islets of hormone-sensitive lipase deficient mice impairs insulin secretion. Biochem. Biophys. Res. Commun. 376 (2008) 558-562
88. Fex M., Haemmerle G., Wierup N., Dekker-Nitert M., Rehn M., Ristow M., Zechner R., Sundler F., Holm C., Eliasson L., and Mulder H. A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis. Diabetologia 52 (2009) 271-280
89. Haemmerle G., Lass A., Zimmermann R., Gorkiewicz G., Meyer C., Rozman J., Heldmaier G., Maier R., Theussl C., Eder S., Kratky D., Wagner E.F., Klingenspor M., Hoefler G., and Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312 (2006) 734-737
90. Reid B.N., Ables G.P., Otlivanchik O.A., Schoiswohl G., Zechner R., Blaner W.S., Goldberg I.J., Schwabe R.F., Chua S.C., and Huang L.S. Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J. Biol. Chem. 283 (2008) 13087-13099
91. Huijsman E., van de Par C., Economou C., van der Poel C., Lynch G.S., Schoiswohl G., Haemmerle G., Zechner R., and Watt M.J. Adipose triacylglycerol lipase deletion alters whole body energy metabolism and impairs exercise performance in mice. Am. J. Physiol. Endocrinol. Metab. 297 (2009) E505-E513
92. Watt M.J., van Denderen B.J., Castelli L.A., Bruce C.R., Hoy A.J., Kraegen E.W., Macaulay L., and Kemp B.E. Adipose triglyceride lipase regulation of skeletal muscle lipid metabolism and insulin responsiveness. Mol. Endocrinol. 22 (2008) 1200-1212
93. Peyot M.L., Guay C., Latour M.G., Lamontagne J., Lussier R., Pineda M., Ruderman N.B., Haemmerle G., Zechner R., Joly E., Madiraju S.R., Poitout V., and Prentki M. Adipose triglyceride lipase is implicated in fuel- and non-fuel-stimulated insulin secretion. J. Biol. Chem. 284 (2009) 16848-16859
94. Moitra J., Mason M.M., Olive M., Krylov D., Gavrilova O., Marcus-Samuels B., Feigenbaum L., Lee E., Aoyama T., Eckhaus M., Reitman M.L., and Vinson C. Life without white fat: a transgenic mouse. Genes Dev. 12 (1998) 3168-3181
95. Trujillo M.E., Pajvani U.B., and Scherer P.E. Apoptosis through targeted activation of caspase 8 ("ATTAC-mice"): novel mouse models of inducible and reversible tissue ablation. Cell. Cycle. 4 (2005) 1141-1145
96. Sabin M.A., Stewart C.E., Crowne E.C., Turner S.J., Hunt L.P., Welsh G.I., Grohmann M.J., Holly J.M., and Shield J.P. Fatty acid-induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid. J. Cell. Physiol. 211 (2007) 244-252
97. Maedler K., Oberholzer J., Bucher P., Spinas G.A., and Donath M.Y. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52 (2003) 726-733
98. Listenberger L.L., Han X., Lewis S.E., Cases S., Farese Jr. R.V., Ory D.S., and Schaffer J.E. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 3077-3082
99. Nadra K., de Preux Charles A.S., Medard J.J., Hendriks W.T., Han G.S., Gres S., Carman G.M., Saulnier-Blache J.S., Verheijen M.H., and Chrast R. Phosphatidic acid mediates demyelination in Lpin1 mutant mice. Genes Dev. 22 (2008) 1647-1661
100. Samuel V.T., Liu Z.X., Wang A., Beddow S.A., Geisler J.G., Kahn M., Zhang X.M., Monia B.P., Bhanot S., and Shulman G.I. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J. Clin. Invest. 117 (2007) 739-745
101. Yu C., Chen Y., Zong H., Wang Y., Bergeron R., Kim J.K., Cline G.W., Cushman S.W., Cooney G.J., Atcheson B., White M.F., Kraegen E.W., and Shulman G.I. Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 2 (2002) 2
102. Holland W.L., Brozinick J.T., Wang L.P., Hawkins E.D., Sargent K.M., Liu Y., Narra K., Hoehn K.L., Knotts T.A., Siesky A., Nelson D.H., Karathanasis S.K., Fontenot G.K., Birnbaum M.J., and Summers S.A. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell. Metab. 5 (2007) 167-179
103. Hoehn K.L., Hohnen-Behrens C., Cederberg A., Wu L.E., Turner N., Yuasa T., Ebina Y., and James D.E. IRS1-independent defects define major nodes of insulin resistance. Cell. Metab. 7 (2008) 421-433
104. Taniguchi C.M., Kondo T., Sajan M., Luo J., Bronson R., Asano T., Farese R., Cantley L.C., and Kahn C.R. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell. Metab. 3 (2006) 343-353
105. Cazzolli R., Mitchell T.W., Burchfield J.G., Pedersen D.J., Turner N., Biden T.J., and Schmitz-Peiffer C. Dilinoleoyl-phosphatidic acid mediates reduced IRS-1 tyrosine phosphorylation in rat skeletal muscle cells and mouse muscle. Diabetologia 50 (2007) 1732-1742
106. Wakelam M.J. Diacylglycerol-when is it an intracellular messenger?. Biochim. Biophys. Acta 1436 (1998) 117-126
107. Bartke N., and Hannun Y.A. Bioactive sphingolipids: metabolism and function. J. Lipid. Res. 50 Suppl (2009) S91-S96
108. Hanada K., Kumagai K., Tomishige N., and Yamaji T. CERT-mediated trafficking of ceramide. Biochim. Biophys. Acta 1791 (2009) 684-691
109. Holland W.L., and Summers S.A. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev. 29 (2008) 381-402
110. Hanada K. Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim. Biophys. Acta 1632 (2003) 16-30
111. Shimabukuro M., Higa M., Zhou Y.T., Wang M.Y., Newgard C.B., and Unger R.H. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J. Biol. Chem. 273 (1998) 32487-32490
112. Shimabukuro M., Zhou Y.T., Levi M., and Unger R.H. Fatty acid-induced b cell apoptosis: a link between obesity and diabetes. Proc. Natl. Acad. Sci. USA. 95 (1998) 2498-2502
113. Unger R.H., and Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim. Biophys. Acta 1585 (2002) 202-212
114. Yang G.D., Badeanlou L., Bielawski J.D., Roberts A.J., Hannun Y.A., and Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297 1 (2009) E211-E224
115. Cazzolli R., Carpenter L., Biden T.J., and Schmitz-Peiffer C. A role for protein phosphatase 2A-like activity, but not atypical protein kinase Czeta, in the inhibition of protein kinase B/Akt and glycogen synthesis by palmitate. Diabetes 50 (2001) 2210-2218
116. Watson M.L., Coghlan M., and Hundal H.S. Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells. Biochem. J. 417 (2009) 791-801
117. Chavez J.A., Knotts T.A., Wang L.P., Li G., Dobrowsky R.T., Florant G.L., and Summers S.A. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J. Biol. Chem. 13 (2003) 10297-10303
118. Glaros E.N., Kim W.S., Quinn C.M., Jessup W., Rye K.A., and Garner B. Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice. J. Lipid. Res. 49 (2008) 324-331
119. Deevska G.M., Rozenova K.A., Giltiay N.V., Chambers M.A., White J., Boyanovsky B.B., Wei J., Daugherty A., Smart E.J., Reid M.B., Merrill A.H., and Nikolova-Karakashian M. Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice. J. Biol. Chem. 284 (2009) 8359-8368
120. Hojjati M., Li Z., Zhou H., Tang S., Huan C., Ooi E., Lu S., and Jiang X.C. Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J. Biol. Chem. 280 11 (2004) 10284-10289
121. Park T.S., Panek R.L., Mueller S.B., Hanselman J.C., Rosebury W.S., Robertson A.W., Kindt E.K., Homan R., Karathanasis S.K., and Rekhter M.D. Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 110 (2004) 3465-3471
122. Glaros E.N., Kim W.S., Wu B.J., Suarna C., Quinn C.M., Rye K.A., Stocker R., Jessup W., and Garner B. Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration. Biochem. Pharmacol. 73 (2007) 1340-1346
123. Park T.s., Hu Y., Okajima K., Buchanan J., Homma S., Davidson M.M., Abel E.D., Jiang X.C., and Goldberg I.J. Abstract 1386: Inhibition of ceramide biosynthesis decreases cardiomyopathy in lipoprotein lipase (LpL) lipotoxicity 116 (2007) II_284-II_285
124. Hojjati M.R., Li Z., and Jiang X.C. Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice. Biochim. Biophys. Acta 1737 (2005) 44-51
125. Zheng W., Kollmeyer J., Symolon H., Momin A., Munter E., Wang E., Kelly S., Allegood J.C., Liu Y., Peng Q., Ramaraju H., Sullards M.C., Cabot M., and Merrill Jr. A.H. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim. Biophys. Acta 1758 (2006) 1864-1884
126. Yang Q., Graham T.E., Mody N., Preitner F., Peroni O.D., Zabolotny J.M., Kotani K., Quadro L., and Kahn B.B. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436 (2005) 356-362
127. Aerts J.M., Ottenhoff R., Powlson A.S., Grefhorst A., van Eijk M., Dubbelhuis P.F., Kuipers F., Serlie M.J., Wennekes T., Overkleeft H.S., Sethi J.K., and O'Rahilly S. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56 5 (2007) 1341-1349
128. Zhao H., Przybylska M., Wu I.H., Zhang J., Siegel C., Komarnitsky S., Yew N.S., and Cheng S.H. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56 (2007) 1210-1218
129. Zhao H., Przybylska M., Wu I.H., Zhang J., Maniatis P., Pacheco J., Piepenhagen P., Copeland D., Arbeeny C., Shayman J.A., Aerts J.M., Jiang C., Cheng S.H., and Yew N.S. Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology 50 (2009) 85-93
130. Glaros E.N., Kim W.S., Rye K.A., Shayman J.A., and Garner B. Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice. J. Lipid. Res. 49 (2008) 1677-1681
131. Yamashita T., Hashiramoto A., Haluzik M., Mizukami H., Beck S., Norton A., Kono M., Tsuji S., Daniotti J.L., Werth N., Sandhoff R., Sandhoff K., and Proia R.L. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 3445-3449
132. Li C.M., Park J.H., Simonaro C.M., He X., Gordon R.E., Friedman A.H., Ehleiter D., Paris F., Manova K., Hepbiloikler S., Fuks Z., Sandhoff K., Kolesnick R., and Schuchman E.H. Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics 79 (2002) 218-224
133. Stratford S., Hoehn K.L., Liu F., and Summers S.A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem. 279 (2004) 36608-36615
134. Chavez J.A., Knotts T.A., Wang L.P., Li G., Dobrowsky R.T., Florant G.L., and Summers S.A. 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
135. Li X., Monks B., Ge Q., and Birnbaum M.J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447 (2007) 1012-1016
136. JeBailey L., Wanono O., Niu W., Roessler J., Rudich A., and Klip A. Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. Diabetes 56 (2007) 394-403
137. Kashkar H., Wiegmann K., Yazdanpanah B., Haubert D., and Kronke M. Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane. J. Biol. Chem. 280 (2005) 20804-20813
138. Birbes H., Bawab S.E., Obeid L.M., and Hannun Y.A. Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv. Enzyme. Regul. 42 (2002) 113-129
139. Birbes H., El Bawab S., Hannun Y.A., and Obeid L.M. Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. Faseb. J. 15 (2001) 2669-2679
140. Birbes H., Luberto C., Hsu Y.T., El Bawab S., Hannun Y.A., and Obeid L.M. A mitochondrial pool of sphingomyelin is involved in TNFalpha-induced Bax translocation to mitochondria. Biochem. J. 386 (2005) 445-451
141. Garcia-Ruiz C., Colell A., Mari M., Morales A., and Fernandez-Checa J.C. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J. Biol. Chem. 272 (1997) 11369-11377
142. Gudz T.I., Tserng K.Y., and Hoppel C.L. Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J. Biol. Chem. 272 (1997) 24154-24158
143. Cacicedo J.M., Benjachareowong S., Chou E., Ruderman N.B., and Ido Y. Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes 54 (2005) 1838-1845
144. Li H., Junk P., Huwiler A., Burkhardt C., Wallerath T., Pfeilschifter J., and Forstermann U. Dual effect of ceramide on human endothelial cells: induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase. Circulation 106 (2002) 2250-2256
145. Gulbins E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol. Res. 47 (2003) 393-399
146. Gulbins E., and Grassme H. Ceramide and cell death receptor clustering. Biochim. Biophys. Acta 1585 (2002) 139-145
147. Gulbins E., and Kolesnick R. Raft ceramide in molecular medicine. Oncogene 22 (2003) 7070-7077
148. Siskind L.J., Feinstein L., Yu T., Davis J.S., Jones D., Choi J., Zuckerman J.E., Tan W., Hill R.B., Hardwick J.M., and Colombini M. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J. Biol. Chem. 283 11 (2008) 6622-6630
149. Siskind L.J., Kolesnick R.N., and Colombini M. Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6 (2006) 118-125
150. Siskind L.J., Fluss S., Bui M., and Colombini M. Sphingosine forms channels in membranes that differ greatly from those formed by ceramide. J. Bioenerg. Biomembr. 37 (2005) 227-236
151. Siskind L.J. Mitochondrial ceramide and the induction of apoptosis. J. Bioenerg. Biomembr. 37 (2005) 143-153
152. Siskind L.J., Davoody A., Lewin N., Marshall S., and Colombini M. Enlargement and contracture of C2-ceramide channels. Biophys. J. 85 (2003) 1560-1575
153. Siskind L.J., Kolesnick R.N., and Colombini M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J. Biol. Chem. 277 (2002) 26796-26803
154. Siskind L.J., and Colombini M. The lipids C2- and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem. 275 (2000) 38640-38644
155. Boden G. Ceramide: a contributor to insulin resistance or an innocent bystander?. Diabetologia 51 (2008) 1095-1096
156. Minehira K., Young S.G., Villanueva C.J., Yetukuri L., Oresic M., Hellerstein M.K., Farese Jr. R.V., Horton J.D., Preitner F., Thorens B., and Tappy L. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J. Lipid. Res. 49 (2008) 2038-2044
157. Aerts J.M., Ottenhoff R., Powlson A.S., Grefhorst A., van Eijk M., Dubbelhuis P.F., Aten J., Kuipers F., Serlie M.J., Wennekes T., Sethi J.K., O'Rahilly S., and Overkleeft H.S. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56 (2007) 1341-1349
158. Tagami S., Inokuchi Ji J., Kabayama K., Yoshimura H., Kitamura F., Uemura S., Ogawa C., Ishii A., Saito M., Ohtsuka Y., Sakaue S., and Igarashi Y. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 277 (2002) 3085-3092
159. Randle P.J., Garland P.B., Hales L.N., and Newsholme E.A. The glucose fatty acid cycle, its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet i (1963) 785-789
160. Roden M., Price T.B., Perseghin G., Petersen K.F., Rothman D.L., Cline G.W., and Shulman G.I. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97 (1996) 2859-2865
161. Dumas J.F., Simard G., Flamment M., Ducluzeau P.H., and Ritz P. Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans?. Diabetes. Metab. 35 (2009) 159-167
162. Turner N., and Heilbronn L.K. Is mitochondrial dysfunction a cause of insulin resistance?. Trends Endocrinol. Metab. 19 (2008) 324-330
163. Dobbins R.L., Szczepaniak L.S., Bentley B., Esser V., Myhill J., and McGarry J.D. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50 (2001) 123-130
164. Bruce C.R., Hoy A.J., Turner N., Watt M.J., Allen T.L., Carpenter K., Cooney G.J., Febbraio M.A., and Kraegen E.W. 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
165. Abu-Elheiga L., Matzuk M.M., Kordari P., Oh W., Shaikenov T., Gu Z., and Wakil S.J. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 12011-12016
166. Abu-Elheiga L., Matzuk M.M., Abo-Hashema K.A., and Wakil S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291 (2001) 2613-2616
167. Choi C.S., Savage D.B., Abu-Elheiga L., Liu Z.X., Kim S., Kulkarni A., Distefano A., Hwang Y.J., Reznick R.M., Codella R., Zhang D., Cline G.W., Wakil S.J., and Shulman G.I. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 16480-16485
168. Schreurs M., van Dijk T.H., Gerding A., Havinga R., Reijngoud D.J., and Kuipers F. Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. Diabetes Obes. Metab. (2009)
169. Wakil S.J., and Abu-Elheiga L.A. Fatty acid metabolism: target for metabolic syndrome. J. Lipid. Res. 50 Suppl (2009) S138-S143
170. Mao J., DeMayo F.J., Li H., Abu-Elheiga L., Gu Z., Shaikenov T.E., Kordari P., Chirala S.S., Heird W.C., and Wakil S.J. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 8552-8557
171. Harada N., Oda Z., Hara Y., Fujinami K., Okawa M., Ohbuchi K., Yonemoto M., Ikeda Y., Ohwaki K., Aragane K., Tamai Y., and Kusunoki J. Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol. Cell. Biol. 27 (2007) 1881-1888
172. Savage D.B., Choi C.S., Samuel V.T., Liu Z.X., Zhang D., Wang A., Zhang X.M., Cline G.W., Yu X.X., Geisler J.G., Bhanot S., Monia B.P., and Shulman G.I. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J. Clin. Invest. 116 (2006) 817-824
173. Koves T.R., Ussher J.R., Noland R.C., Slentz D., Mosedale M., Ilkayeva O., Bain J., Stevens R., Dyck J.R., Newgard C.B., Lopaschuk G.D., and Muoio D.M. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell. Metab. 7 (2008) 45-56
174. Turner N., Bruce C.R., Beale S.M., Hoehn K.L., So T., Rolph M.S., and Cooney G.J. 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 (2007) 2085-2092
175. Holloway G.P., Benton C.R., Mullen K.L., Yoshida Y., Snook L.A., Han X.X., Glatz J.F., Luiken J.J., Lally J., Dyck D.J., and Bonen A. In obese rat muscle transport of palmitate is increased and is channeled to triacylglycerol storage despite an increase in mitochondrial palmitate oxidation. Am. J. Physiol. Endocrinol. Metab. 296 (2009) E738-747
176. Holloway G.P., Thrush A.B., Heigenhauser G.J., Tandon N.N., Dyck D.J., Bonen A., and Spriet L.L. Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. Am. J. Physiol. Endocrinol. Metab. 292 (2007) E1782-1789
177. Boushel R., Gnaiger E., Schjerling P., Skovbro M., Kraunsoe R., and Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50 (2007) 790-796
178. Muoio D.M., and Newgard C.B. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat. Rev. Mol. Cell. Biol. 9 (2008) 193-205
179. Muoio D.M., and Newgard C.B. Fatty acid oxidation and insulin action: when less is more. Diabetes 57 (2008) 1455-1456
180. Bouzakri K., Austin R., Rune A., Lassman M.E., Garcia-Roves P.M., Berger J.P., Krook A., Chibalin A.V., Zhang B.B., and Zierath J.R. Malonyl coenzymeA decarboxylase regulates lipid and glucose metabolism in human skeletal muscle. Diabetes 57 (2008) 1508-1516
181. An J., Muoio D.M., Shiota M., Fujimoto Y., Cline G.W., Shulman G.I., Koves T.R., Stevens R., Millington D., and Newgard C.B. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10 (2004) 268-274
182. Chirala S.S., Chang H., Matzuk M., Abu-Elheiga L., Mao J., Mahon K., Finegold M., and Wakil S.J. Fatty acid synthesis is essential in embryonic development: fatty acid synthase null mutants and most of the heterozygotes die in utero. Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 6358-6363
183. Lopez M., and Vidal-Puig A. Brain lipogenesis and regulation of energy metabolism. Curr. Opin. Clin. Nutr. Metab. Care. 11 (2008) 483-490
184. Chakravarthy M.V., Zhu Y., Lopez M., Yin L., Wozniak D.F., Coleman T., Hu Z., Wolfgang M., Vidal-Puig A., Lane M.D., and Semenkovich C.F. Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. J. Clin. Invest. 117 (2007) 2539-2552
185. Chakravarthy M.V., Zhu Y., Yin L., Coleman T., Pappan K.L., Marshall C.A., McDaniel M.L., and Semenkovich C.F. Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation. J. Lipid. Res. 50 (2009) 630-640
186. Chakravarthy M.V., Pan Z., Zhu Y., Tordjman K., Schneider J.G., Coleman T., Turk J., and Semenkovich C.F. "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell. Metab. 1 (2005) 309-322
187. Kraegen E.W., Bruce C., Hegarty B.D., Ye J.M., Turner N., and Cooney G. AMP-activated protein kinase and muscle insulin resistance. Front. Biosci. 14 (2009) 4658-4672
188. Hegarty B.D., Turner N., Cooney G.J., and Kraegen E.W. Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase. Acta Physiol. (Oxf). 196 (2009) 129-145
189. Power R.A., Hulver M.W., Zhang J.Y., Dubois J., Marchand R.M., Ilkayeva O., Muoio D.M., and Mynatt R.L. Carnitine revisited: potential use as adjunctive treatment in diabetes. Diabetologia 50 (2007) 824-832
190. Houstis N., Rosen E.D., and Lander E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440 (2006) 944-948