Not all fats are created equal: adipose vs. ectopic fat, implication in cardiometabolic diseases

References

1. Kissebah AH, Freedman DS, Peiris AN. Health risks of obesity. Med Clin North Am 1989;73:111–38.10.1016/S0025-7125(16)30695-2Search in Google Scholar

2. Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 1990;10:497–511.10.1161/01.ATV.10.4.497Search in Google Scholar PubMed

3. Pouliot MC, Despres JP, Nadeau A, Moorjani S, Prud’Homme D, Lupien PJ, Tremblay A, Bouchard C. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes 1992;41:826–34.10.2337/diab.41.7.826Search in Google Scholar PubMed

4. Turkoglu C, Duman BS, Gunay D, Cagatay P, Ozcan R, Buyukdevrim AS. Effect of abdominal obesity on insulin resistance and the components of the metabolic syndrome: evidence supporting obesity as the central feature. Obes Surg 2003;13:699–705.10.1381/096089203322509255Search in Google Scholar PubMed

5. Sironi AM, Petz R, De Marchi D, Buzzigoli E, Ciociaro D, Positano V, Lombardi M, Ferrannini E, Gastaldelli A. Impact of increased visceral and cardiac fat on cardiometabolic risk and disease. Diabet Med 2012;29:622–7.10.1111/j.1464-5491.2011.03503.xSearch in Google Scholar PubMed

6. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–56.10.1210/jc.2004-0395Search in Google Scholar PubMed

7. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 2006;55:1537–45.10.2337/db06-0263Search in Google Scholar PubMed

8. Walker GE, Marzullo P, Ricotti R, Bona G, Prodam F. The pathophysiology of abdominal adipose tissue depots in health and disease. Horm Mol Biol Clin Investig 2014;19:57–74.10.1515/hmbci-2014-0023Search in Google Scholar PubMed

9. Morelli M, Gaggini M, Daniele G, Marraccini P, Sicari R, Gastaldelli A. Ectopic fat: the true culprit linking obesity and cardiovascular disease? Thromb Haemost 2013;110:651–60.10.1160/TH13-04-0285Search in Google Scholar PubMed

10. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome – an allostatic perspective. Biochim Biophys Acta 2010;1801:338–49.10.1016/j.bbalip.2009.12.006Search in Google Scholar PubMed

11. Bays H. Central obesity as a clinical marker of adiposopathy; increased visceral adiposity as a surrogate marker for global fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014;21: 345–51.10.1097/MED.0000000000000093Search in Google Scholar PubMed PubMed Central

12. Nedergaard J, Cannon B. How brown is brown fat? It depends where you look. Nat Med 2013;19:540–1.10.1038/nm.3187Search in Google Scholar PubMed

13. Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014;10:24–36.10.1038/nrendo.2013.204Search in Google Scholar PubMed

14. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013;27:234–50.10.1101/gad.211649.112Search in Google Scholar PubMed PubMed Central

15. Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev 1998;78:783–809.10.1152/physrev.1998.78.3.783Search in Google Scholar PubMed

16. Zhang H, Qiu X, Shindel AW, Ning H, Ferretti L, Jin X, Lin G, Lin CS, Lue TF. Adipose tissue-derived stem cells ameliorate diabetic bladder dysfunction in a type II diabetic rat model. Stem Cells Dev 2012;21:1391–400.10.1089/scd.2011.0244Search in Google Scholar PubMed PubMed Central

17. Ravussin E, Galgani JE. The implication of brown adipose tissue for humans. Annual Rev Nutr 2011;31:33–47.10.1146/annurev-nutr-072610-145209Search in Google Scholar PubMed PubMed Central

18. Avram AS, Avram MM, James WD. Subcutaneous fat in normal and diseased states: 2. Anatomy and physiology of white and brown adipose tissue. J Am Acad Dermatol 2005;53:671–83.10.1016/j.jaad.2005.05.015Search in Google Scholar PubMed

19. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, Madeo F. Fat signals – lipases and lipolysis in lipid metabolism and signaling. Cell Metab 2012;15:279–91.10.1016/j.cmet.2011.12.018Search in Google Scholar PubMed PubMed Central

20. Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329–39.10.1079/PNS200194Search in Google Scholar PubMed

21. Alligier M, Gabert L, Meugnier E, Lambert-Porcheron S, Chanseaume E, Pilleul F, Debard C, Sauvinet V, Morio B, Vidal-Puig A, Vidal H, Laville M. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab 2013;98:802–10.10.1210/jc.2012-3289Search in Google Scholar PubMed

22. Johannsen DL, Tchoukalova Y, Tam CS, Covington JD, Xie W, Schwarz JM, Bajpeyi S, Ravussin E. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the “adipose tissue expandability” hypothesis. Diabetes Care 2014;37:2789–97.10.2337/dc14-0761Search in Google Scholar PubMed PubMed Central

23. Sironi AM, Gastaldelli A, Mari A, Ciociaro D, Positano V, Buzzigoli E, Ghione S, Turchi S, Lombardi M, Ferrannini E. Visceral fat in hypertension: influence on insulin resistance and beta-cell function. Hypertension 2004;44:127–33.10.1161/01.HYP.0000137982.10191.0aSearch in Google Scholar PubMed

24. Nicklas BJ, Rogus EM, Colman EG, Goldberg AP. Visceral adiposity, increased adipocyte lipolysis, and metabolic dysfunction in obese postmenopausal women. Am J Physiol 1996;270:E72–8.10.1152/ajpendo.1996.270.1.E72Search in Google Scholar PubMed

25. Jeong SK, Kim YK, Park JW, Shin YJ, Kim DS. Impact of visceral fat on the metabolic syndrome and non-alcoholic fatty liver disease. J Korean Med Sci 2008;23:789–95.10.3346/jkms.2008.23.5.789Search in Google Scholar PubMed PubMed Central

26. Despres JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation 2012;126:1301–13.10.1161/CIRCULATIONAHA.111.067264Search in Google Scholar PubMed

27. Gastaldelli A, Basta G. Ectopic fat and cardiovascular disease: what is the link? Nutr Metab Cardiovasc Dis 2010;20:481–90.10.1016/j.numecd.2010.05.005Search in Google Scholar PubMed

28. 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;88:5163–8.10.1210/jc.2003-030698Search in Google Scholar PubMed

29. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, Ouyang P, Espeland MA, Lohman KK, Criqui MH, Allison M, Bluemke DA, Carr JJ. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr 2009;90:499–504.10.3945/ajcn.2008.27358Search in Google Scholar PubMed PubMed Central

30. Gastaldelli A, Morales MA, Marraccini P, Sicari R. The role of cardiac fat in insulin resistance. Curr Opin Clin Nutr Metab Care 2012;15:523–8.10.1097/MCO.0b013e328358be7bSearch in Google Scholar PubMed

31. Iozzo P. Myocardial, perivascular, and epicardial fat. Diabetes Care 2011;34 (Suppl 2):S371–9.10.2337/dc11-s250Search in Google Scholar PubMed PubMed Central

32. 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 calcification in a community-based sample: the Framingham Heart Study. Circulation 2008;117:605–13.10.1161/CIRCULATIONAHA.107.743062Search in Google Scholar PubMed

33. Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig 2014;19:25–37.10.1515/hmbci-2014-0022Search in Google Scholar PubMed

34. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500–8.10.1056/NEJMoa0808718Search in Google Scholar PubMed

35. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518–25.10.1056/NEJMoa0808949Search in Google Scholar PubMed

36. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–17.10.1056/NEJMoa0810780Search in Google Scholar PubMed PubMed Central

37. Richard D, Monge-Roffarello B, Chechi K, Labbe SM, Turcotte EE. Control and physiological determinants of sympathetically mediated brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 2012;3:36.10.3389/fendo.2012.00036Search in Google Scholar PubMed PubMed Central

38. Svensson PA, Lindberg K, Hoffmann JM, Taube M, Pereira MJ, Mohsen-Kanson T, Hafner AL, Rizell M, Palming J, Dani C, Svensson MK. Characterization of brown adipose tissue in the human perirenal depot. Obesity (Silver Spring) 2014;22:1830–7.10.1002/oby.20765Search in Google Scholar PubMed

39. Sacks HS, Fain JN, Holman B, Cheema P, Chary A, Parks F, Karas J, Optican R, Bahouth SW, Garrett E, Wolf RY, Carter RA, Robbins T, Wolford D, Samaha J. Uncoupling protein-1 and related messenger ribonucleic acids in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J Clin Endocrinol Metab 2009;94:3611–5.10.1210/jc.2009-0571Search in Google Scholar PubMed

40. Cinti S. The role of brown adipose tissue in human obesity. Nutr Metab Cardiovasc Dis 2006;16:569–74.10.1016/j.numecd.2006.07.009Search in Google Scholar PubMed

41. Bjorndal B, Burri L, Staalesen V, Skorve J, Berge RK. Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obes 2011;2011:490650.10.1155/2011/490650Search in Google Scholar PubMed PubMed Central

42. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol 2004;24:3057–67.10.1128/MCB.24.7.3057-3067.2004Search in Google Scholar PubMed PubMed Central

43. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 2015;125:478–86.10.1172/JCI78362Search in Google Scholar PubMed PubMed Central

44. Morrison SF, Madden CJ, Tupone D. Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab 2014;19:741–56.10.1016/j.cmet.2014.02.007Search in Google Scholar PubMed PubMed Central

45. Reddy NL, Tan BK, Barber TM, Randeva HS. Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity. BMC Obesity 2014;1:13.10.1186/s40608-014-0013-5Search in Google Scholar PubMed PubMed Central

46. Wang CZ, Wei D, Guan MP, Xue YM. Triiodothyronine regulates distribution of thyroid hormone receptors by activating AMP-activated protein kinase in 3T3-L1 adipocytes and induces uncoupling protein-1 expression. Mol Cell Biochem 2014;393:247–54.10.1007/s11010-014-2067-6Search in Google Scholar PubMed

47. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1 alpha and browning of white adipose tissues in adaptive thermogenesis. Gene Dev 2012;26:271–81.10.1101/gad.177857.111Search in Google Scholar PubMed PubMed Central

48. Qian SW, Tang Y, Li X, Liu Y, Zhang YY, Huang HY, Xue RD, Yu HY, Guo L, Gao HD, Liu Y, Sun X, Li YM, Jia WP, Tang QQ. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA 2013;110:E798–807.10.1073/pnas.1215236110Search in Google Scholar PubMed PubMed Central

49. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302–9.10.1016/j.cmet.2013.12.017Search in Google Scholar PubMed PubMed Central

50. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463–8.10.1038/nature10777Search in Google Scholar PubMed PubMed Central

51. Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014;157:1279–91.10.1016/j.cell.2014.03.065Search in Google Scholar PubMed PubMed Central

52. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150:366–76.10.1016/j.cell.2012.05.016Search in Google Scholar PubMed PubMed Central

53. Fitzgibbons TP, Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc 2014;3:e000582.10.1161/JAHA.113.000582Search in Google Scholar PubMed PubMed Central

54. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 2000;279:C670–81.10.1152/ajpcell.2000.279.3.C670Search in Google Scholar PubMed

55. Vitali A, Murano I, Zingaretti MC, Frontini A, Ricquier D, Cinti S. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J Lipid Res 2012;53:619–29.10.1194/jlr.M018846Search in Google Scholar PubMed PubMed Central

56. Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes 2010;34(Suppl 1):S36–42.10.1038/ijo.2010.182Search in Google Scholar PubMed PubMed Central

57. Loyd C, Obici S. Brown fat fuel use and regulation of energy homeostasis. Curr Opin Clin Nutr Metab Care 2014;17:368–72.10.1097/MCO.0000000000000063Search in Google Scholar PubMed

58. Ravussin Y, Xiao C, Gavrilova O, Reitman ML. Effect of intermittent cold exposure on brown fat activation, obesity, and energy homeostasis in mice. PLoS One 2014;9:e85876.10.1371/journal.pone.0085876Search in Google Scholar PubMed PubMed Central

59. Cypess AM, Kahn CR. Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes 2010;17:143–9.10.1097/MED.0b013e328337a81fSearch in Google Scholar PubMed PubMed Central

60. Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, Zhang C, Seki T, Hosaka K, Wahlberg E, Yang J, Zhang L, Lanne T, Sun B, Li X, Liu Y, Zhang Y, Cao Y. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab 2013;18:118–29.10.1016/j.cmet.2013.06.003Search in Google Scholar PubMed PubMed Central

61. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerback S, Virtanen KA. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011;14:272–9.10.1016/j.cmet.2011.06.012Search in Google Scholar PubMed

62. Hanssen MJ, Wierts R, Hoeks J, Gemmink A, Brans B, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance. Diabetologia 2015;58:586–95.10.1007/s00125-014-3465-8Search in Google Scholar PubMed

63. Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013;123:215–23.10.1172/JCI62308Search in Google Scholar PubMed PubMed Central

64. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Hoeks J, Schrauwen P, van Marken Lichtenbelt WD. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 2012;97:E1229–33.10.1210/jc.2012-1289Search in Google Scholar PubMed

65. Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerback S, Rissanen A, Pietilainen KH, Virtanen KA. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity (Silver Spring) 2013;21:2279–87.10.1002/oby.20456Search in Google Scholar PubMed

66. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011;17:200–5.10.1038/nm.2297Search in Google Scholar PubMed

67. Iwen KA, Wenzel ET, Ott V, Perwitz N, Wellhoner P, Lehnert H, Dodt C, Klein J. Cold-induced alteration of adipokine profile in humans. Metabolism: clinical and experimental. Metabolism 2011;60:430–7.10.1016/j.metabol.2010.03.011Search in Google Scholar PubMed

68. Gastaldelli A. Visceral adipose tissue and ectopic fat deposition. In: Bray GA, Bouchard C, editors. Handbook of obesity: etiology and pathophysiology. 3rd ed. CRC Press 2014;237–48.Search in Google Scholar

69. Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C, Zhang J, Wu J, Zeng R, Chen YE. Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation 2012;126:1067–78.10.1161/CIRCULATIONAHA.112.104489Search in Google Scholar PubMed PubMed Central

70. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 2010;53:1270–87.10.1007/s00125-010-1684-1Search in Google Scholar

71. van Herpen NA, Schrauwen-Hinderling VB. Lipid accumulation in non-adipose tissue and lipotoxicity. Physiol Behav 2008;94:231–41.10.1016/j.physbeh.2007.11.049Search in Google Scholar PubMed

72. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 2013;5:1544–60.10.3390/nu5051544Search in Google Scholar PubMed PubMed Central

73. Misra VL, Khashab M, Chalasani N. Non-alcoholic fatty liver disease and cardiovascular risk. Curr Gastroenterol Rep 2009;11:50–5.10.1007/s11894-009-0008-4Search in Google Scholar PubMed PubMed Central

74. Bugianesi E, Gastaldelli A. Hepatic and cardiac steatosis: are they coupled? Heart Fail Clin 2012;8:663–70.10.1016/j.hfc.2012.06.010Search in Google Scholar PubMed

75. Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, Mitrakou A, Balkau B, Investigators R. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 2009;49:1537–44.10.1002/hep.22845Search in Google Scholar PubMed

76. Targher G, Bertolini L, Padovani R, Poli F, Scala L, Tessari R, Zenari L, Falezza G. Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet Med 2006;23:403–9.10.1111/j.1464-5491.2006.01817.xSearch in Google Scholar PubMed

77. Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with non-alcoholic fatty liver disease. Hepatology 2012;55:1389–97.10.1002/hep.25539Search in Google Scholar PubMed

78. Nseir W, Shalata A, Marmor A, Assy N. Mechanisms linking non-alcoholic fatty liver disease with coronary artery disease. Dig Dis Sci 2011;56:3439–49.10.1007/s10620-011-1767-ySearch in Google Scholar PubMed

79. Villanova N, Moscatiello S, Ramilli S, Bugianesi E, Magalotti D, Vanni E, Zoli M, Marchesini G. Endothelial dysfunction and cardiovascular risk profile in non-alcoholic fatty liver disease. Hepatology 2005;42:473–80.10.1002/hep.20781Search in Google Scholar PubMed

80. Targher G. Non-alcoholic fatty liver disease as a determinant of cardiovascular disease. Atherosclerosis 2007;190:18–9; author reply 20–1.10.1016/j.atherosclerosis.2006.06.004Search in Google Scholar PubMed

81. Kozakova M, Palombo C, Eng MP, Dekker J, Flyvbjerg A, Mitrakou A, Gastaldelli A, Ferrannini E, Investigators R. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques. Hepatology 2012;55:1406–15.10.1002/hep.25555Search in Google Scholar PubMed

82. DeFronzo RA. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. Int J Clin Pract Suppl 2004;143:9–21.10.1111/j.1368-504X.2004.00389.xSearch in Google Scholar PubMed

83. Taylor R. Banting Memorial lecture 2012: reversing the twin cycles of type 2 diabetes. Diabet Med 2013;30:267–75.10.1111/dme.12039Search in Google Scholar PubMed PubMed Central

84. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 1999;276:E977–89.10.1152/ajpendo.1999.276.5.E977Search in Google Scholar PubMed

85. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999;42:113–6.10.1007/s001250051123Search in Google Scholar PubMed

86. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Haring HU. Association of increased intramyocellular lipid content with insulin resistance in lean non-diabetic offspring of type 2 diabetic subjects. Diabetes 1999;48:1113–9.10.2337/diabetes.48.5.1113Search in Google Scholar PubMed

87. Krssak M, Roden M. The role of lipid accumulation in liver and muscle for insulin resistance and type 2 diabetes mellitus in humans. Rev Endocr Metab Disord 2004;5:127–34.10.1023/B:REMD.0000021434.98627.dcSearch in Google Scholar

88. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care 2013;36(Suppl 2):S127–38.10.2337/dcS13-2011Search in Google Scholar PubMed PubMed Central

89. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 2010;285:7153–64.10.1074/jbc.M109.053942Search in Google Scholar PubMed PubMed Central

90. Petrovic N, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Thermogenically competent non-adrenergic recruitment in brown preadipocytes by a PPARgamma agonist. Am J Physiol Endocrinol Metab 2008;295:E287–96.10.1152/ajpendo.00035.2008Search in Google Scholar PubMed

91. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med 2013;19:557–66.10.1038/nm.3159Search in Google Scholar PubMed PubMed Central

92. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17:819–37.10.1016/j.cmet.2013.04.008Search in Google Scholar PubMed

93. Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, Ananthakrishnan G, Rohner-Jeanrenaud F, Drucker DJ, DiMarchi R, Rahmouni K, Oldfield BJ, Tschop MH, Perez-Tilve D. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 2012;61:2753–62.10.2337/db11-1556Search in Google Scholar PubMed PubMed Central

94. Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Ferno J, Salvador J, Escalada J, Dieguez C, Lopez M, Fruhbeck G, Nogueiras R. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014;63:3346–58.10.2337/db14-0302Search in Google Scholar PubMed