Adipose tissue biology and cardiomyopathy: Translational implications

Circulation Research

Volumn 111, Issue 12, 2012, Pages 1565-1577

  Turer, Aslan T ^a,b   Hill, Joseph A ^a,b   Elmquist, Joel K ^a,b   Scherer, Philipp E ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

adipokines; adipose; diabetes mellitus; heart failure; insulin sensitivity; obesity

Indexed keywords

ADIPOCYTOKINE; ADIPONECTIN; COLLAGEN TYPE 7; LEPTIN; RESISTIN;

ADIPOSE TISSUE; BROWN ADIPOSE TISSUE; CARDIOMYOPATHY; CARDIOVASCULAR DISEASE; HEART FAILURE; HEART MUSCLE CELL; HEART PROTECTION; HUMAN; INSULIN RESISTANCE; LIPOTOXICITY; METABOLIC SYNDROME X; MOLECULAR MECHANICS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW;

ADIPOKINES; ADIPOSE TISSUE; ANIMALS; CARDIOMYOPATHIES; HUMANS; INSULIN RESISTANCE; OBESITY; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84871536826     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.111.262493     Document Type: Review

References (184)

1. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation. 2012;125:e2-e220.
2. Deng Y, Scherer PE. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci. 2010;1212:E1-E19.
3. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006;55:1537-1545. (Pubitemid 44324105)
4. Suganami T, Tanaka M, Ogawa Y. Adipose tissue infammation and ecto-pic lipid accumulation [Review]. Endocr J. 2012;59:849-857.
5. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094-2101.
6. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defnes mac-rophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46:2347-2355. (Pubitemid 41532523)
7. Murano I, Rutkowski JM, Wang QA, Cho YR, Scherer PE, Cinti S. Time course of histomorphological changes in adipose tissue upon acute li-poatrophy. Nutr Metab Cardiovasc Dis. 2012.
8. Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profle through expansion of adipose tissue. J Clin Invest. 2007;117:2621-2637. (Pubitemid 47494363)
9. Asterholm IW, Halberg N, Scherer PE. Mouse Models of Lipodystrophy Key reagents for the understanding of the metabolic syndrome. Drug Discov Today Dis Models. 2007;4:17-24. (Pubitemid 350286531)
10. Halberg N, Wernstedt-Asterholm I, Scherer PE. The adipocyte as an endocrine cell. Endocrinol Metab Clin North Am. 2008;37:753-68, x.
11. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-432. (Pubitemid 24365442)
12. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest. 2011;121:2087-2093.
13. Tartaglia LA, Dembski M, Weng X, et al. Identifcation and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263-1271. (Pubitemid 26007816)
14. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA. 1996;93:8374-8378. (Pubitemid 26269565)
15. Al-Qassab H, Smith MA, Irvine EE, et al. Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab. 2009;10:343-354.
16. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413:794-795. (Pubitemid 33026839)
17. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270:26746-26749.
18. Shapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol. 1998;8:335-338. (Pubitemid 28159119)
19. Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol Sci. 2009;30:234-239.
20. Turer AT, Scherer PE. Adiponectin: mechanistic insights and clinical implications. Diabetologia. 2012;55:2319-2326.
21. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang Cc C, Itani SI, Lodish HF, Ruderman NB. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA. 2002;99:16309-16313. (Pubitemid 35462791)
22. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288-1295. (Pubitemid 35373562)
23. Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332-339. (Pubitemid 46376688)
24. Miller RA, Chu Q, Le Lay J, Scherer PE, Ahima RS, Kaestner KH, Foretz M, Viollet B, Birnbaum MJ. Adiponectin suppresses gluconeo-genic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J Clin Invest. 2011;121:2518-2528.
25. Holland WL, Miller RA, Wang ZV, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011;17:55-63.
26. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312. (Pubitemid 32151228)
27. Barnes KM, Miner JL. Role of resistin in insulin sensitivity in rodents and humans. Curr Protein Pept Sci. 2009;10:96-107.
28. Aigner T, Hambach L, Söder S, Schlötzer-Schrehardt U, Pöschl E. The C5 domain of Col6A3 is cleaved off from the Col6 fbrils immediately after secretion. Biochem Biophys Res Commun. 2002;290:743-748. (Pubitemid 34687503)
29. Pasarica M, Gowronska-Kozak B, Burk D, Remedios I, Hymel D, Gimble J, Ravussin E, Bray GA, Smith SR. Adipose tissue collagen VI in obesity. J Clin Endocrinol Metab. 2009;94:5155-5162.
30. Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA. Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fbrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab. 2010;299:E1016-E1027.
31. Park J, Scherer PE. Adipocyte-derived endotrophin promotes malignant tumor progression. J Clin Inv. 2012;122:4243-4256.
32. Cohade C, Mourtzikos KA, Wahl RL. "USA-Fat": prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J Nucl Med. 2003;44:1267-1270. (Pubitemid 39655187)
33. Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci USA. 2012;109:5874-5879.
34. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myo-kine that drives brown-fat-like development of white fat and thermogen-esis. Nature. 2012;481:463-468.
35. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122:1022-1036.
36. Gburcik V, Cawthorn WP, Nedergaard J, Timmons JA, Cannon B. An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes. Am J Physiol Endocrinol Metab. 2012;303:E1053-E1060.
37. Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, "brite, " and white adipose tissues. Am J Physiol Endocrinol Metab. 2012;302:E19-E31.
38. Wu J, Boström P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366-376.
39. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83:847-850. (Pubitemid 28496456)
40. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145:2273-2282. (Pubitemid 38535056)
41. Krief S, Lönnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ. Tissue distribution of beta 3-ad-renergic receptor mRNA in man. J Clin Invest. 1993;91:344-349. (Pubitemid 23037290)
42. Rebuffé-Scrive M, Andersson B, Olbe L, Björntorp P. Metabolism of adipose tissue in intraabdominal depots of nonobese men and women. Metab Clin Exp. 1989;38:453-458. (Pubitemid 19125880)
43. Ostman J, Arner P, Engfeldt P, Kager L. Regional differences in the control of lipolysis in human adipose tissue. Metab Clin Exp. 1979;28:1198-1205. (Pubitemid 10181708)
44. Hellmér J, Marcus C, Sonnenfeld T, Arner P. Mechanisms for differences in lipolysis between human subcutaneous and omental fat cells. J Clin Endocrinol Metab. 1992;75:15-20.
45. Mauriege P, Galitzky J, Berlan M, Lafontan M. Heterogeneous distribution of beta and alpha-2 adrenoceptor binding sites in human fat cells from various fat deposits: functional consequences. Eur J Clin Invest. 1987;17:156-165. (Pubitemid 17060030)
46. Bolinder J, Kager L, Ostman J, Arner P. Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis. Diabetes. 1983;32:117-123. (Pubitemid 13180343)
47. Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest. 1993;92:2191-2198. (Pubitemid 23333523)
48. Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA. 2012;308:1150-1159.
49. Vega GL, Adams-Huet B, Peshock R, Willett D, Shah B, Grundy SM. Infuence of body fat content and distribution on variation in metabolic risk. J Clin Endocrinol Metab. 2006;91:4459-4466. (Pubitemid 44833423)
50. Turer AT, Khera A, Ayers CR, Turer CB, Grundy SM, Vega GL, Scherer PE. Adipose tissue mass and location affect circulating adiponectin levels. Diabetologia. 2011;54:2515-2524.
51. Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Yudkin JS, Heine RJ, Nijpels G, Seidell JC; Hoorn study. Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels: the Hoorn study. Diabetes Care. 2004;27:372-377. (Pubitemid 38174060)
52. Koster A, Stenholm S, Alley DE, Kim LJ, Simonsick EM, Kanaya AM, Visser M, Houston DK, Nicklas BJ, Tylavsky FA, Satterfeld S, Goodpaster BH, Ferrucci L, Harris TB; Health ABC Study. Body fat distribution and infammation among obese older adults with and without metabolic syndrome. Obesity (Silver Spring). 2010;18:2354-2361.
53. Romero-Corral A, Somers VK, Sierra-Johnson J, Korenfeld Y, Boarin S, Korinek J, Jensen MD, Parati G, Lopez-Jimenez F. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J. 2010;31:737-746.
54. Kosmala W, Jedrzejuk D, Derzhko R, Przewlocka-Kosmala M, Mysiak A, Bednarek-Tupikowska G. Left ventricular function impairment in patients with normal-weight obesity: contribution of abdominal fat deposition, profbrotic state, reduced insulin sensitivity, and proinfammatory activation. Circ Cardiovasc Imaging. 2012;5:349-356.
55. Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96:3313-3325.
56. Al-Shali KZ, Hegele RA. Laminopathies and atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:1591-1595. (Pubitemid 39180880)
57. Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 2000;85:1776-1782. (Pubitemid 32269275)
58. Lupsa BC, Sachdev V, Lungu AO, Rosing DR, Gorden P. Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. Medicine (Baltimore). 2010;89:245-250.
59. Iacobellis G, Malavazos AE. Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: the Jackson Heart Study: comment on Liu et Al. Diabetes Care. 2010;33:e127; author reply e128.
60. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med. 2005;2:536-543. (Pubitemid 41670345)
61. Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O'Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcifcation in a community-based sample: the Framingham Heart Study. Circulation. 2008;117:605-613.
62. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, Di Mario U, Leonetti F. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk. J Clin Endocrinol Metab. 2003;88:5163-5168. (Pubitemid 37452712)
63. Liu J, Fox CS, Hickson DA, May WL, Ding J, Carr JJ, Taylor HA. Pericardial fat and echocardiographic measures of cardiac abnormalities: the Jackson Heart Study. Diabetes Care. 2011;34:341-346.
64. Konishi M, Sugiyama S, Sugamura K, Nozaki T, Matsubara J, Akiyama E, Utsunomiya D, Matsuzawa Y, Yamashita Y, Kimura K, Umemura S, Ogawa H. Accumulation of pericardial fat correlates with left ventricular diastolic dysfunction in patients with normal ejection fraction. J Cardiol. 2012;59:344-351.
65. Kim TH, Yu SH, Choi SH, Yoon JW, Kang SM, Chun EJ, Choi SI, Shin H, Lee HK, Park KS, Jang HC, Lim S. Pericardial fat amount is an independent risk factor of coronary artery stenosis assessed by multidetector-row computed tomography: the Korean Atherosclerosis Study 2. Obesity (Silver Spring). 2011;19:1028-1034.
66. Cheng VY, Dey D, Tamarappoo B, Nakazato R, Gransar H, Miranda-Peats R, Ramesh A, Wong ND, Shaw LJ, Slomka PJ, Berman DS. Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging. 2010;3:352-360.
67. Nakanishi R, Rajani R, Cheng VY, Gransar H, Nakazato R, Shmilovich H, Otaki Y, Hayes SW, Thomson LE, Friedman JD, Slomka PJ, Berman DS, Dey D. Increase in epicardial fat volume is associated with greater coronary artery calcifcation progression in subjects at intermediate risk by coronary calcium score: a serial study using non-contrast cardiac CT. Atherosclerosis. 2011;218:363-368.
68. Tamarappoo B, Dey D, Shmilovich H, Nakazato R, Gransar H, Cheng VY, Friedman JD, Hayes SW, Thomson LE, Slomka PJ, Rozanski A, Berman DS. Increased pericardial fat volume measured from noncon-trast CT predicts myocardial ischemia by SPECT. JACC Cardiovasc Imaging. 2010;3:1104-1112.
69. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M. Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol. 2011;58:248-255.
70. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, Sarov-Blat L, O'Brien S, Keiper EA, Johnson AG, Martin J, Goldstein BJ, Shi Y. Human epicardial adipose tissue is a source of infammatory mediators. Circulation. 2003;108:2460-2466. (Pubitemid 37444406)
71. Fujikawa T, Chuang JC, Sakata I, Ramadori G, Coppari R. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci USA. 2010;107:17391-17396.
72. Rahmouni K. Obesity, sympathetic overdrive, and hypertension: the leptin connection. Hypertension. 2010;55:844-845.
73. Correia ML, Morgan DA, Sivitz WI, Mark AL, Haynes WG. Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure. Hypertension. 2001;37:936-942. (Pubitemid 32221617)
74. Rahmouni K, Morgan DA. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension. 2007;49:647-652.
75. do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension. 2011;57:918-926.
76. Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS. Adiponectin acts in the brain to decrease body weight. Nat Med. 2004;10:524-529. (Pubitemid 38667912)
77. Kosari S, Rathner JA, Chen F, Kosari S, Badoer E. Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue. Endocrinology. 2011;152:2626-2633.
78. Ahima RS. Central actions of adipocyte hormones. Trends Endocrinol Metab. 2005;16:307-313. (Pubitemid 41206637)
79. Luiken JJ, Koonen DP, Willems J, Zorzano A, Becker C, Fischer Y, Tandon NN, Van Der Vusse GJ, Bonen A, Glatz JF. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes. 2002;51:3113-3119.
80. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009;297:E578-E591.
81. Wende AR, Abel ED. Lipotoxicity in the heart. Biochim Biophys Acta. 2010;1801:311-319.
82. Khullar M, Al-Shudiefat AA, Ludke A, Binepal G, Singal PK. Oxidative stress: a key contributor to diabetic cardiomyopathy. Can J Physiol Pharmacol. 2010;88:233-240.
83. Holland WL, Summers SA. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev. 2008;29:381-402. (Pubitemid 351831506)
84. Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim Biophys Acta. 2010;1801:1-22.
85. Liu GX, Hanley PJ, Ray J, Daut J. Long-chain acyl-coenzyme A esters and fatty acids directly link metabolism to K(ATP) channels in the heart. Circ Res. 2001;88:918-924. (Pubitemid 32441470)
86. Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS, Yoon YS, Yoon G, Choi KM, Ko YG. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia. 2006;49:784-791. (Pubitemid 43361881)
87. Brookheart RT, Michel CI, Schaffer JE. As a matter of fat. Cell Metab. 2009;10:9-12.
88. Dobrin JS, Lebeche D. Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev Cardiovasc Ther. 2010;8:373-391.
89. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004;25:543-567. (Pubitemid 39096070)
90. Wang Y, Nishina PM, Naggert JK. Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng. J Endocrinol. 2009;203:65-74.
91. Ueno M, Carvalheira JB, Tambascia RC, Bezerra RM, Amaral ME, Carneiro EM, Folli F, Franchini KG, Saad MJ. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia. 2005;48:506-518. (Pubitemid 40487298)
92. Hartley D, Cooper GM. Role of mTOR in the degradation of IRS-1: regulation of PP2A activity. J Cell Biochem. 2002;85:304-314. (Pubitemid 34274898)
93. Ni YG, Wang N, Cao DJ, Sachan N, Morris DJ, Gerard RD, Kuro-O M, Rothermel BA, Hill JA. FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci USA. 2007;104:20517-20522.
94. Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Metabolic stress-induced activation of FoxO1 triggers diabetic car-diomyopathy in mice. J Clin Invest. 2012;122:1109-1118.
95. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787-790. (Pubitemid 30212409)
96. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA. 2000;97:12222-12226.
97. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002;51:1938-1948. (Pubitemid 34564309)
98. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, Brownlee M. Inhibition of GAPDH activity by poly(ADP-ribose) poly-merase activates three major pathways of hyperglycemic damage in en-dothelial cells. J Clin Invest. 2003;112:1049-1057. (Pubitemid 38056320)
99. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820. (Pubitemid 34000785)
100. Poornima IG, Parikh P, Shannon RP. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006;98:596-605.
101. Kenchaiah S, Sesso HD, Gaziano JM. Body mass index and vigorous physical activity and the risk of heart failure among men. Circulation. 2009;119:44-52.
102. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996-1002. (Pubitemid 32295654)
103. Chen YT, Vaccarino V, Williams CS, Butler J, Berkman LF, Krumholz HM. Risk factors for heart failure in the elderly: a prospective community-based study. Am J Med. 1999;106:605-612. (Pubitemid 29279295)
104. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305-313. (Pubitemid 34815352)
105. Turkbey EB, McClelland RL, Kronmal RA, Burke GL, Bild DE, Tracy RP, Arai AE, Lima JA, Bluemke DA. The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). JACC Cardiovasc Imaging. 2010;3:266-274.
106. Powell BD, Redfeld MM, Bybee KA, Freeman WK, Rihal CS. Association of obesity with left ventricular remodeling and diastolic dysfunction in patients without coronary artery disease. Am J Cardiol. 2006;98:116-120. (Pubitemid 43902691)
107. Lauer MS, Anderson KM, Levy D. Separate and joint infuences of obesity and mild hypertension on left ventricular mass and geometry: the Framingham Heart Study. J Am Coll Cardiol. 1992;19:130-134.
108. Lauer MS, Anderson KM, Kannel WB, Levy D. The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study. JAMA. 1991;266:231-236.
109. Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie ME, Messier V, Sladek R, Rabasa-Lhoret R. Characterizing the profle of obese patients who are metabolically healthy. Int J Obes (Lond). 2011;35:971-981.
110. Mitsuhashi H, Yatsuya H, Tamakoshi K, Matsushita K, Otsuka R, Wada K, Sugiura K, Takefuji S, Hotta Y, Kondo T, Murohara T, Toyoshima H. Adiponectin level and left ventricular hypertrophy in Japanese men. Hypertension. 2007;49:1448-1454. (Pubitemid 46809393)
111. McManus DD, Lyass A, Ingelsson E, Massaro JM, Meigs JB, Aragam J, Benjamin EJ, Vasan RS. Relations of circulating resistin and adiponec-tin and cardiac structure and function: the Framingham Offspring Study. Obesity (Silver Spring). 2012;20:1882-1886.
112. Gustafsson S, Lind L, Zethelius B, Venge P, Flyvbjerg A, Söderberg S, Ingelsson E. Adiponectin and cardiac geometry and function in elderly: results from two community-based cohort studies. Eur J Endocrinol. 2010;162:543-550.
113. Bidulescu A, Liu J, Musani SK, Fox ER, Samdarshi TE, Sarpong DF, Vaccarino V, Wilson PW, Arnett DK, Din-Dzietham R, Taylor HA, Gibbons GH. Association of adiponectin with left ventricular mass in blacks: the Jackson Heart Study. Circ Heart Fail. 2011;4:747-753.
114. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K, Funahashi T, Colucci WS, Walsh K. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004;10:1384-1389. (Pubitemid 40022722)
115. Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, de Divitiis O, Varricchio M. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension. 1999;34:1047-1052.
116. Lieb W, Sullivan LM, Aragam J, Harris TB, Roubenoff R, Benjamin EJ, Vasan RS. Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age. Am J Cardiol. 2009;104:602-605.
117. Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003;93:277-279. (Pubitemid 37048239)
118. Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108:754-759. (Pubitemid 36999263)
119. Kang S, Chemaly ER, Hajjar RJ, Lebeche D. Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. J Biol Chem. 2011;286:18465-18473.
120. Frankel DS, Vasan RS, D'Agostino RB Sr, Benjamin EJ, Levy D, Wang TJ, Meigs JB. Resistin, adiponectin, and risk of heart failure the Framingham offspring study. J Am Coll Cardiol. 2009;53:754-762.
121. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Obesity and risk of incident heart failure in older men with and without pre-existing coronary heart disease: does leptin have a role? J Am Coll Cardiol. 2011;58:1870-1877.
122. Lieb W, Sullivan LM, Harris TB, Roubenoff R, Benjamin EJ, Levy D, Fox CS, Wang TJ, Wilson PW, Kannel WB, Vasan RS. Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals. Diabetes Care. 2009;32:612-616.
123. Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd-Jones DM, Shahar E, Szklo M, Lima JA. Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008;51:1775-1783. (Pubitemid 351608497)
124. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, Safftz JE, Schaffer JE. A novel mouse model of lipotoxic cardiomyopathy. J Clin Invest. 2001;107:813-822. (Pubitemid 32274034)
125. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, Seo T, Hu Y, Lutz EP, Merkel M, Bensadoun A, Homma S, Goldberg IJ. Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest. 2003;111:419-426. (Pubitemid 36182219)
126. Glenn DJ, Wang F, Nishimoto M, Cruz MC, Uchida Y, Holleran WM, Zhang Y, Yeghiazarians Y, Gardner DG. A murine model of isolated cardiac steatosis leads to cardiomyopathy. Hypertension. 2011;57:216-222.
127. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac phe-notype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109:121-130. (Pubitemid 34052548)
128. Son NH, Park TS, Yamashita H, Yokoyama M, Huggins LA, Okajima K, Homma S, Szabolcs MJ, Huang LS, Goldberg IJ. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. J Clin Invest. 2007;117:2791-2801. (Pubitemid 47529610)
129. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA. 2000;97:1784-1789. (Pubitemid 30118520)
130. Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W, King GL. Preferential elevation of protein kinase C isoform beta II and diacylglyc-erol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA. 1992;89:11059-11063.
131. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectros-copy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462-E468. (Pubitemid 40110657)
132. Thomsen C, Becker U, Winkler K, Christoffersen P, Jensen M, Henriksen O. Quantifcation of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging. 1994;12:487-495. (Pubitemid 24113193)
133. Longo R, Pollesello P, Ricci C, Masutti F, Kvam BJ, Bercich L, Crocè LS, Grigolato P, Paoletti S, de Bernard B. Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis. J Magn Reson Imaging. 1995;5:281-285.
134. Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D'Ambrosia G, Arbique D, Vongpatanasin W, Unger R, Victor RG. Myocardial tri-glycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn Reson Med. 2003;49:417-423. (Pubitemid 36262808)
135. McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, Levine BD, Raskin P, Victor RG, Szczepaniak LS. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation. 2007;116:1170-1175. (Pubitemid 47360218)
136. Iozzo P, Lautamaki R, Borra R, Lehto HR, Bucci M, Viljanen A, Parkka J, Lepomaki V, Maggio R, Parkkola R, Knuuti J, Nuutila P. Contribution of glucose tolerance and gender to cardiac adiposity. J Clin Endocrinol Metab. 2009;94:4472-4482.
137. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol. 2008;52:1793-1799.
138. Korosoglou G, Humpert PM, Ahrens J, Oikonomou D, Osman NF, Gitsioudis G, Buss SJ, Steen H, Schnackenburg B, Bierhaus A, Nawroth P P, Katus HA. Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve. J Magn Reson Imaging. 2012;35:804-811.
139. McGavock J, Szczepaniak LS, Ayers CR, Abdullah SM, See R, Gore MO, Drazner MH, de Lemos JA, McGuire DK. The effects of rosi-glitazone on myocardial triglyceride content in patients with type 2 diabetes: a randomised, placebo-controlled trial. Diab Vasc Dis Res. 2012;9:131-137.
140. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol. 2001;38:789-795. (Pubitemid 32835754)
141. Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin M; ADHERE
142. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F, Kosiborod M, Portnay EL, Sokol SI, Bader F, Krumholz HM. The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med. 2005;165:55-61. (Pubitemid 40096082)
143. Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. J Card Fail. 2011;17:374-380.
144. Güder G, Frantz S, Bauersachs J, Allolio B, Wanner C, Koller MT, Ertl G, Angermann CE, Störk S. Reverse epidemiology in systolic and non-systolic heart failure: cumulative prognostic beneft of classical cardiovascular risk factors. Circ Heart Fail. 2009;2:563-571.
145. Lafontan M, Moro C, Sengenes C, Galitzky J, Crampes F, Berlan M. An unsuspected metabolic role for atrial natriuretic peptides: the control of lipolysis, lipid mobilization, and systemic nonesterifed fatty acids levels in humans. Arterioscler Thromb Vasc Biol. 2005;25:2032-2042. (Pubitemid 41416298)
146. Lafontan M, Langin D. Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res. 2009;48:275-297.
147. Nørrelund H, Wiggers H, Halbirk M, Frystyk J, Flyvbjerg A, Bøtker HE, Schmitz O, Jørgensen JO, Christiansen JS, Møller N. Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failure. J Intern Med. 2006;260:11-21. (Pubitemid 43894065)
148. Lommi J, Kupari M, Yki-Järvinen H. Free fatty acid kinetics and oxidation in congestive heart failure. Am J Cardiol. 1998;81:45-50. (Pubitemid 28046841)
149. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093-1129. (Pubitemid 40894649)
150. Tsutamoto T, Tanaka T, Sakai H, Ishikawa C, Fujii M, Yamamoto T, Horie M. Total and high molecular weight adiponectin, haemodynam-ics, and mortality in patients with chronic heart failure. Eur Heart J. 2007;28:1723-1730. (Pubitemid 47227093)
151. McEntegart MB, Awede B, Petrie MC, Sattar N, Dunn FG, MacFarlane NG, McMurray JJ. Increase in serum adiponectin concentration in patients with heart failure and cachexia: relationship with leptin, other cy-tokines, and B-type natriuretic peptide. Eur Heart J. 2007;28:829-835. (Pubitemid 47343601)
152. Masson S, Gori F, Latini R, Milani V, Flyvbjerg A, Frystyk J, Crociati L, Pietri S, Vago T, Barlera S, Maggioni AP, Tognoni G, Tavazzi L, Omland T, Franzosi MG; GISSI-HF Investigators. Adiponectin in chronic heart failure: infuence of diabetes and genetic variants. Eur J Clin Invest. 2011;41:1330-1338.
153. Kistorp C, Faber J, Galatius S, Gustafsson F, Frystyk J, Flyvbjerg A, Hildebrandt P. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-1762. (Pubitemid 41372115)
154. Khan RS, Kato TS, Chokshi A, Chew M, Yu S, Wu C, Singh P, Cheema FH, Takayama H, Harris C, Reyes-Soffer G, Knöll R, Milting H, Naka Y, Mancini D, Schulze PC. Adipose tissue infammation and adiponectin resistance in patients with advanced heart failure: correction after ventricular assist device implantation. Circ Heart Fail. 2012;5:340-348.
155. Xydas S, Rosen RS, Ng C, Mercando M, Cohen J, DiTullio M, Magnano A, Marboe CC, Mancini DM, Naka Y, Oz MC, Maybaum S. Mechanical unloading leads to echocardiographic, electrocardiographic, neurohor-monal, and histologic recovery. J Heart Lung Transplant. 2006;25:7-15. (Pubitemid 43049658)
156. Thompson LO, Skrabal CA, Loebe M, Lafuente JA, Roberts RR, Akgul A, Jones V, Bruckner BA, Thohan V, Noon GP, Youker KA. Plasma neu-rohormone levels correlate with left ventricular functional and morphological improvement in LVAD patients. J Surg Res. 2005;123:25-32. (Pubitemid 40094641)
157. Milting H, EL Banayosy A, Kassner A, Fey O, Sarnowski P, Arusoglu L, Thieleczek R, Brinkmann T, Kleesiek K, Körfer R. The time course of natriuretic hormones as plasma markers of myocardial recovery in heart transplant candidates during ventricular assist device support reveals differences among device types. J Heart Lung Transplant. 2001;20:949-955. (Pubitemid 32824140)
158. Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, Askew GR, Simcox JA, McClain DA, Li C, Scherer PE. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012;18:1539-1549.
159. Mullen KL, Pritchard J, Ritchie I, Snook LA, Chabowski A, Bonen A, Wright D, Dyck DJ. Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats. Am J Physiol Regul Integr Comp Physiol. 2009;296:R243-R251.
160. Yamaji M, Tsutamoto T, Tanaka T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M, Horie M. Effect of carperitide on plasma adipo-nectin levels in acute decompensated heart failure patients with diabetes mellitus. Circ J. 2009;73:2264-2269.
161. Tsukamoto O, Fujita M, Kato M, Yamazaki S, Asano Y, Ogai A, Okazaki H, Asai M, Nagamachi Y, Maeda N, Shintani Y, Minamino T, Asakura M, Kishimoto I, Funahashi T, Tomoike H, Kitakaze M. Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure. J Am Coll Cardiol. 2009;53:2070-2077.
162. Wang Y, Lau WB, Gao E, Tao L, Yuan Y, Li R, Wang X, Koch WJ, Ma XL. Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury. Am J Physiol Endocrinol Metab. 2010;298:E663-E670.
163. Ding G, Qin Q, He N, Francis-David SC, Hou J, Liu J, Ricks E, Yang Q. Adiponectin and its receptors are expressed in adult ventricular car-diomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. J Mol Cell Cardiol. 2007;43:73-84. (Pubitemid 46898422)
164. Skurk C, Wittchen F, Suckau L, Witt H, Noutsias M, Fechner H, Schultheiss HP, Poller W. Description of a local cardiac adiponectin system and its deregulation in dilated cardiomyopathy. Eur Heart J. 2008;29:1168-1180. (Pubitemid 351844892)
165. Schulze PC, Kratzsch J, Linke A, Schoene N, Adams V, Gielen S, Erbs S, Moebius-Winkler S, Schuler G. Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure. Eur J Heart Fail. 2003;5:33-40. (Pubitemid 36205542)
166. Bobbert P, Jenke A, Bobbert T, Kühl U, Rauch U, Lassner D, Scheibenbogen C, Poller W, Schultheiss HP, Skurk C. High leptin and resistin expression in chronic heart failure: adverse outcome in patients with dilated and infammatory cardiomyopathy. Eur J Heart Fail. 2012;14:1265-1275.
167. McGaffn KR, Moravec CS, McTiernan CF. Leptin signaling in the failing and mechanically unloaded human heart. Circ Heart Fail. 2009;2:676-683.
168. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, Noon GP, Frazier OH, Taegtmeyer H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 2004;18:1692-1700. (Pubitemid 39463708)
169. Chokshi A, Drosatos K, Cheema FH, Ji R, Khawaja T, Yu S, Kato T, Khan R, Takayama H, Knöll R, Milting H, Chung CS, Jorde U, Naka Y, Mancini DM, Goldberg IJ, Schulze PC. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation. 2012;125:2844-2853.
170. Stamou SC, Nussbaum M, Stiegel RM, Reames MK, Skipper ER, Robicsek F, Lobdell KW. Effect of body mass index on outcomes after cardiac surgery: is there an obesity paradox? Ann Thorac Surg. 2011;91:42-47.
171. Lancefeld T, Clark DJ, Andrianopoulos N, Brennan AL, Reid CM, Johns J, Freeman M, Charter K, Duffy SJ, Ajani AE, Proietto J, Farouque O; MIG (Melbourne Interventional Group) Registry. Is there an obesity paradox after percutaneous coronary intervention in the contemporary era? An analysis from a multicenter Australian registry. JACC Cardiovasc Interv. 2010;3:660-668.
172. Hastie CE, Padmanabhan S, Slack R, Pell AC, Oldroyd KG, Flapan AD, Jennings KP, Irving J, Eteiba H, Dominiczak AF, Pell JP. Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention. Eur Heart J. 2010;31:222-226.
173. Bucholz EM, Rathore SS, Reid KJ, Jones PG, Chan PS, Rich MW, Spertus JA, Krumholz HM. Body mass index and mortality in acute myocardial infarction patients. Am J Med. 2012;125:796-803.
174. Angerås O, Albertsson P, Karason K, Råmunddal T, Matejka G, James S, Lagerqvist B, Rosengren A, Omerovic E. Evidence for obesity paradox in patients with acute coronary syndromes: a report from the Swedish Coronary Angiography and Angioplasty Registry. Eur Heart J. In press.
175. Vemmos K, Ntaios G, Spengos K, Savvari P, Vemmou A, Pappa T, Manios E, Georgiopoulos G, Alevizaki M. Association between obesity and mortality after acute frst-ever stroke: the obesity-stroke paradox. Stroke. 2011;42:30-36.
176. Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC. Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke. 2011;42:3397-3402.
177. Sohn MW, Budiman-Mak E, Oh EH, Park MS, Stuck RM, Stone NJ, Pearce WB. Obesity paradox in amputation risk among nonelderly diabetic men. Obesity (Silver Spring). 2012;20:460-462.
178. Diercks DB, Roe MT, Mulgund J, Pollack CV Jr, Kirk JD, Gibler WB, Ohman EM, Smith SC Jr, Boden WE, Peterson ED. The obesity paradox in non-ST-segment elevation acute coronary syndromes: results from the Can Rapid risk stratifcation of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines Quality Improvement Initiative. Am Heart J. 2006;152:140-148. (Pubitemid 44040849)
179. Mehta RH, Califf RM, Garg J, White HD, Van de Werf F, Armstrong PW, Pieper KS, Topol EJ, Granger CB. The impact of anthropomorphic indices on clinical outcomes in patients with acute ST-elevation myocar-dial infarction. Eur Heart J. 2007;28:415-424. (Pubitemid 47343554)
180. Lavie CJ, Milani RV, Ventura HO. Obesity and the "obesity paradox" in cardiovascular diseases. Clin Pharmacol Ther. 2011;90:23-25.
181. Berglund ED, Vianna CR, Donato J Jr, Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P, Brule LJ, Scott MM, Coppari R, Elmquist JK. Direct leptin action on POMC neurons regulates glucose homeo-stasis and hepatic insulin sensitivity in mice. J Clin Invest. 2012; 122:1000-1009.
182. Liu L, Shi X, Bharadwaj KG, Ikeda S, Yamashita H, Yagyu H, Schaffer JE, Yu YH, Goldberg IJ. DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. J Biol Chem. 2009;284:36312-36323.
183. Son NH, Yu S, Tuinei J, Arai K, Hamai H, Homma S, Shulman GI, Abel ED, Goldberg IJ. PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα defciency despite increases in fatty acid oxidation. J Clin Invest. 2010;120:3443-3454.
184. Turer AT. Using metabolomics to assess myocardial metabolism and energetics in heart failure. J Mol Cell Cardiol. In press.