What is metabolic syndrome, and why are children getting it?

Annals of the New York Academy of Sciences

Volumn 1281, Issue 1, 2013, Pages 123-140

  Weiss, Ram ^a   Bremer, Andrew A ^b   Lustig, Robert H ^c,d  

^a HEBREW UNIVERSITY   (Israel)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Diet; Insulin resistance; Metabolic syndrome; Obesity; Reactive oxygen species

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; ADIPONECTIN RECEPTOR 1; ADIPONECTIN RECEPTOR 2; BRANCHED CHAIN AMINO ACID; C REACTIVE PROTEIN; FATTY ACID; HYDROCORTISONE; INTERLEUKIN 6; LEPTIN; REACTIVE OXYGEN METABOLITE;

ABDOMINAL OBESITY; ADIPOSE TISSUE; ALCOHOL CONSUMPTION; ARTICLE; ATHEROGENESIS; CARBOHYDRATE INTAKE; CARDIOVASCULAR RISK; CHILDHOOD DISEASE; DISORDERS OF CARBOHYDRATE METABOLISM; DYSLIPIDEMIA; ENDOPLASMIC RETICULUM STRESS; ENDOTHELIAL DYSFUNCTION; ENVIRONMENTAL FACTOR; FAT BODY; FAT INTAKE; FATTY ACID BLOOD LEVEL; FOOD INTAKE; HUMAN; HYDROCORTISONE BLOOD LEVEL; HYDROCORTISONE RELEASE; HYPERTENSION; HYPOTHALAMUS HYPOPHYSIS ADRENAL SYSTEM; INSULIN CLEARANCE; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID DIET; LIPID METABOLISM; LIPID STORAGE; LIVER CELL; METABOLIC SYNDROME X; MUSCLE; NONHUMAN; OBESITY; PATHOGENESIS; PHENOTYPE; SIGNAL TRANSDUCTION; SLEEP DEPRIVATION; STRESS; SUBCUTANEOUS FAT; UNFOLDED PROTEIN RESPONSE;

EID: 84875686432     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/nyas.12030     Document Type: Article

References (185)

1. Wijnhoven, T.M., J.M. van Raaij, A. Spinelli, et al. in press. WHO European Childhood Obesity Surveillance Initiative 2008: weight, height and body mass index in 6-9-year-old children. Pediatr. Obesity. 012 Sep 21. doi: 10.1111/j.2047-6310.2012.00090.x. [Epub ahead of print].
2. Ogden, C.L., M.D. Carroll, B.K. Kit & K.M. Flegal. 2012. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. JAMA. 307: 483-483.
3. Dietz, W.H. 1998. Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics. 101: 518-525.
4. Must, A. & R.S. Strauss. 1999. Risks and consequences of childhood and adolescent obesity. Int. J. Obes. 23: S2-S11.
5. Styne, D.M. 2001. Childhood and adolescent obesity: prevalence and significance. Pediatr. Clin. N. Am. 48: 823-854.
6. Dietz, W.H. 1998. Health consequences of obesity in youth: childhood predictors of adulthood disease. Pediatrics. 101(supp. 3): 518-525.
7. Tirosh, A., I. Shai, A. Afek, et al. 2011. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N. Engl. J. Med. 364: 1315-1325.
8. Ford, E.S., W.H. Giles & W.H. Dietz. 2002. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 287: 356-359.
9. Must, A., P.F. Jacques, G.E. Dallal, et al. 1992. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N. Engl. J. Med. 327: 1350-1355.
10. Weiss, R., J. Dziura, T.S. Burgert, et al. 2004. Obesity and the metabolic syndrome in children and adolescents. N. Engl. J. Med. 350: 2362-2374.
11. Reaven, G.M. 1988. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595-1607.
12. Cornier, M.A., D. Dabelea, T.L. Hernandez. 2008. The metabolic syndrome. Endocr. Rev. 29: 777-822.
13. Finkelstein, E.A., O.A. Khavjou, H. Thompson, et al. 2012. Obesity and severe obesity forecasts through 2030. Am. J. Prev. Med. 42: 563-570.
14. U.N. General Assembly. 2010. Prevention and control of non-communicable diseases. U.N. General Assembly. New York.
15. Chan, J.M., E.B. Rimm, G.A. Colditz, et al. 1994. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care. 17: 961-969.
16. McLaughlin, T., F. Abbasi, K. Cheal, et al. 2003. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann. Int. Med. 139: 802-809.
17. Abbasi, F., J.W. Chu, C. Lamendola, et al. 2004. Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes. 53: 585-590.
18. Voulgari, C., N. Tentolouris, P. Dilaveris, et al. 2011. Increased heart failure risk in normal-weight people with metabolic syndrome compared with metabolically healthy obese individuals. J. Am. Coll. Cardiol. 58: 1343-1350.
19. Wiegand, S., U. Maikowski, O. Blankenstein, et al. 2004. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity-a problem that is no longer restricted to minority groups. Eur. J. Endocrinol. 151: 199-206.
20. Biltoft, C.A. & A. Muir. 2009. The metabolic syndrome in children and adolescents: a clinician's guide. Adolesc. Med. State Art Rev. 20: 109-120.
21. Albrink, M.J., R.M. Krauss, F.T. Lindgrem, et al. 1980. Intercorrelations among plasma high density lipoprotein, obesity and triglycerides in a normal population. Lipids. 15: 668-676.
22. Despres, J.P. 1993. Abdominal obesity as important component of insulin-resistance syndrome. Nutrition 9: 452-459.
23. Kylin, E. 1923. Studien uber das hypertonie-hyperglyka "mie-hyperurika" miesyndrom. Zentralbl. Inn. Med. 44: 105-127.
24. Luciano, A. & G. Zoppi. 1994. Blood insulin values after the oral glucose tolerance test (OGTT) and the body composition in 30 obese children. Pediatr. Med. Chir. 16: 471-473.
25. Steinberger, J., S.R. Daniels, R.H. Eckel, et al. 2009. Progress and challenges in Metabolic Syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 119: 628-647.
26. Zimmet, P., G. Alberti, F. Kaufman, et al. 2007. International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. The metabolic syndrome in children and adolescents. Lancet 369: 2059-2061.
27. Ford, E.S., C. Li, G. Zhao, et al. 2008. Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes Federation. Diab. Care. 31: 587-589.
28. Hannon, T.S., J. Janosky & S.A. Arslanian. 2006. Longitudinal study of physiologic insulin resistance and metabolic changes of puberty. Ped. Research. 60: 759-763.
29. Moran, A., D.R.J. Jacobs, J., Steinberger, et al. 2008. Changes in insulin resistance and cardiovascular risk during adolescence: establishment of differential risk in males and females. Circulation. 117: 2361-2368.
30. Dai, S., J.E. Fulton, R.B. Harrist, J.A. Grunbaum, et al. 2009. Blood lipids in children: age-related patterns and association with body-fat indices: project HeartBeat! Am. J. Prev. Med. 37(suppl 1): S56-S64.
31. Eisenmann, J.C. 2008. On the use of a continuous metabolic syndrome score in pediatric research. Cardiovasc. Diabetol. 7: 17.
32. Liska, D., S. Dufour, T.L. Zern, et al. 2007. Interethnic differences in muscle, liver and abdominal fat partitioning in obese adolescents. PLoS One 27: e569.
33. Goodman, E., S.R. Daniels, J.B. Meigs & L.M. Dolan. 2007. Instability in the diagnosis of metabolic syndrome in adolescents. Circulation 115: 2316-2322.
34. Weiss, R., M. Shaw, M. Savoye & S. Caprio. 2009. Obesity dynamics and cardiovascular risk factor stability in obese adolescents. Pediatr. Diabetes 10: 360-367.
35. Ogden, C.L., M.D. Carroll, B.K. Kit & K.M. Flegal. 2012. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. JAMA. 307: 483-490.
36. Sinaiko, A.R. & S. Caprio. 2012. Insulin resistance. J. Pediatr. 161: 11-15.
37. Arslanian, S. & C. Suprasongsin. 1996. Differences in the in vivo insulin secretion and sensitivity of healthy black versus white adolescents. J. Pediatr. 129: 440-443.
38. Caprio, S., L.D. Hyman, S. McCarthy, et al. 1996. Fat distribution and cardiovascular risk factors in obese adolescent girls: importance of the intraabdominal fat depot. Am. J. Clin. Nutr. 64: 12-17.
39. Sinha, R., G. Fisch, B. Teague, et al. 2002. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N. Engl. J. Med. 346: 802-810.
40. Sorof, J.M., D. Lai, J. Turner, et al. 2004. Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics 113: 475-482.
41. Steinberger, J. & S.R. Daniels. 2003. Obesity, insulin resistance, diabetes, and cardiovascular risk in children. Circulation 107: 1448-1453.
42. Mimoun, E., Y. Aggoun, M. Pousset, et al. 2008. Association of arterial stiffness and endothelial dysfunction with metabolic syndrome in obese children. J. Pediatr. 153: 65-70.
43. Ode, K.L., B.I. Frohnert & B.M. Nathan. 2009. Identification and treatment of metabolic complications in pediatric obesity. Rev. Endocr. Metab. Disord. 10: 167-188.
44. Abbasi, F., B.W.B. Brown, C. Lamendola, et al. 2002. Relationship between obesity, insulin resistance, and coronary heart disease risk. J. Am. Coll. Cardiol. 40: 937-943.
45. Reinehr, T., R. Wunsch, G. de Sousa & A.M. Toschke. 2008. Relationship between metabolic syndrome definitions for children and adolescents and intima-media thickness. Atherosclerosis 199: 193-200.
46. Morrison, J.A., C.J. Glueck, M. Umar, et al. 2011. Hyperinsulinemia and metabolic syndrome at mean age of 10 years in black and white schoolgirls and development of impaired fasting glucose and type 2 diabetes mellitus by mean age of 24 years. Metabolism 60: 24-31.
47. Weiss, R., S.E. Taksali, W.V. Tamborlane, et al. 2005. Predictors of changes in glucose tolerance status in obese youth. Diab. Care. 28: 902-909.
48. Haffner, S.M. 1999. Epidemiology of insulin resistance and its relation to coronary artery disease. Am. J. Cardiol. 84: 11J-14J.
49. Hu, F.B., J.M. Stampfer, S.M. Haffner, et al. 2002. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diab. Care. 25: 1129-1134.
50. Alberti, K.G. & P.Z. Zimmet. 1998. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15: 539-553.
51. Matsumoto, M., S. Han, T. Kitamura & D. Accili. 2006. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J. Clin. Invest. 116: 2464-2472.
52. Naïmi, M., N. Gautier, C. Chaussade, et al. 2007. Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytes. Endocrinol 148: 2424-2434.
53. Lewis, G.F., K.D. Uffelman, L.W. Szeto & G. Steiner. 1993. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes 42: 833-842.
54. Brown, M.S. & J.L. Goldstein. 2008. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7: 95-96.
55. Bergman, R.N., S.P. Kim, I.R. Hsu, et al. 2007. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular risk. Am. J. Med. 120(Suppl 1): S3-S8.
56. Ross, M.G., I. Huber & M. Desai. 2010. Intrauterine growth restriction, small for gestational age, and experiemental obesity. In Obesity Before Birth: Maternal and Prenatal Effects on the Offspring. R.H. Lustig, Ed.: 215-239. Springer, New York.
57. Ginsberg, H.N., Y.L. Zhang & A. Hernandez-Ono. 2005. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch. Med. Res. 36: 232-240.
58. Samuel, V.T., K.F. Petersen & G.I. Shulman. 2010. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375: 2267-2277.
59. Large, V. & P. Arner. 1998. Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Diabetes Metab. Res. 24: 409-418.
60. Gustafson, B., A. Hammarstedt, C.X. Andersson & U. Smith. 2007. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 27: 2276-2283.
61. Heilbronn, L.K. & L.V. Campbell. 2008. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des. 14: 1225-1230.
62. Roden, M., M. Krssak, H. Stingl, et al. 1999. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes 48: 358-364.
63. Petersen, K.F., S.S.D. Dufour, S. Bilz, et al. 2007. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl. Acad. Sci. 104: 12587-12594.
64. Whincup, P.H., J.A. Gilg, O. Papacosta, et al. 2002. Early evidence of ethnic differences in cardiovascular risk: cross sectional comparison of British South Asian and white children. Br. Med. J. 324: 635.
65. Weiss, R., J.D. Dziura, T.S. Burgert, et al. 2006. Ethnic differences in beta cell adaptation to insulin resistance in obese children and adolescents. Diabetologia 49: 571-579.
66. Moran, A., D.R. Jacobs, J. Steinberger, et al. 1999. Insulin resistance during puberty: results from clamp studies in 357 children. Diabetes 48: 2039-2044.
67. Saad, R.J., K. Danadian, V. Lewy & S.A. Arslanian. 2002. Insulin resistance of puberty in African-American children: lack of a compensatory increase in insulin secretion. Pediatr. Diabetes. 3: 4-9.
68. Bjorntorp, P. 1990. Portal adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis 10: 493-496.
69. Arner, P. 2002. Insulin resistance in type 2 diabetes: role of fatty acids. Diab. Metab. Res. Rev. 18(Supp. 2): S5-S9.
70. Bonora, E. 2000. Relationship between regional fat distribution and insulin resistance. Int. J. Obes. 24(Supp. 2): S32-S35.
71. Koutsari, C. & M.D. Jensen. 2006. Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity. J. Lipid Res. 47: 1643-1650.
72. Abate, N., A. Garg, R.M. Peshock, et al. 1996. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes 45: 1684-1693.
73. Wajchenberg, B.L. 2000. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr. Rev. 21: 697-738.
74. Montague, C.T. & S. O'Rahilly. 2000. The perils of portliness: causes and consequences of visceral adiposity. Diabetes 49: 883-888.
75. Taksali, S.E., S. Caprio, J. Dziura, et al. 2008. High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype. Diabetes 57: 367-371.
76. D'Adamo, E., A.M. Cali, R. Weiss, et al. 2010. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diab. Care. 33: 1817-1822.
77. Ravussin, E. & S.R. Smith. 2002. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann. N.Y. Acad. Sci. 967: 363-378.
78. Sung, K.C. & S.H. Kim. 2011. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J. Clin. Endocrinol. Metab. 96: 1093-1097.
79. Krssak, M., K. Falk Petersen, A. Dresner, et al. 1999. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42: 113-116.
80. Garg, A. 2004. Acquired and inherited lipodystrophies. N. Engl. J. Med. 350: 1220-1234.
81. Goodpaster, B.H., F.L. Thaete, J.A. Simoneau & D.E. Kelley. 1997. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 46: 1579-1585.
82. 13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 48: 1600-1606.
83. Sinha, R., S. Dufour, K.F. Petersen, et al. 2002. Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity. Diabetes 51: 1022-1027.
84. Fabbrini, E., F. Magkos, B.S. Mohammed, et al. 2009. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl. Acad. Sci. 106: 15430-15435.
85. Unger, R.H. 2003. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 144: 5159-5165.
86. Dobbins, R.L., L.S. Szczepaniak, B. Bentley, et al. 2001. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 50: 123-130.
87. Morino, K., K.F. Petersen & G.I. Shulman. 2006. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Supp. 2): S9-S15.
88. Samuel, V.T., Z.X. Liu, X. Qu, et al. 2004. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279: 32345-32353.
89. Hirosumi, J., G. Tuncman, L. Chang, et al. 2002. A central role for JNK in obesity and insulin resistance. Nature 420: 333-336.
90. Zhang, Y., R. Proenca, M. Maffei, et al. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 393: 372-425.
91. Saltiel, A.R. 2001. You are what you secrete. Nat. Med. 7: 887-880.
92. Unger, R.H. 2004. The hyperleptinemia of obesity-regulator of caloric surpluses. Cell 117: 145-146.
93. Arita, Y., S. Kihara, N. Ouchi, et al. 1999. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Comm. 257: 79-83.
94. Kondo, H., I. Shimomura, Y. Matsukawa, et al. 2002. Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 51: 2325-2328.
95. Pajvani, U.B., X. Du, T.P. Combs, et al. 2003. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J. Biol. Chem. 278: 9073-9085.
96. Kadowaki, T. & T. Yamauchi. 2005. Adiponectin and adiponectin receptors. Endocr. Rev. 26: 439-451.
97. Yamauchi, T., J. Kamon, Y. Ito, et al. 2003. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762-769.
98. Ouchi, N., S. Kihara, Y. Arita, et al. 2000. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102: 1296-1301.
99. Yatagai, T., S. Nagasaka, A. Taniguchi, et al. 2003. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism 52: 1274-1278.
100. Hotta, K., T. Funahashi, N.L. Bodkin, et al. 2001. Circulating concentrations of the adipocyte protein adiponectin: a decrease in parallel with reduced insulin sensitivity during the progression of type 2 diabetes in Rhesus monkeys. Diabetes 50: 1126-1133.
101. Weisberg, S.P., D. McCann, M. Desai, et al. 2003. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112: 1673-1808.
102. Matsuzawa, Y., T. Funahashi & T. Nakamura. 1999. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann. N.Y. Acad. Sci. 892: 146-154.
103. Cinti, S., G. Mitchell, G. Barbatelli, et al. 2005. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46: 2347-2355.
104. Yudkin, J.S., M. Kumari, S.E. Humphries & V. Mohamed-Ali. 2000. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link. Atherosclerosis 148: 209-214.
105. Pickup, J.C. & M.A. Crook. 1998. Is type 2 diabetes mellitus a disease of the innate immune system Diabetologia 41: 1241-1248.
106. Ridker, P.M., C.H. Hennekens, J.E. Buring & N. Rifai. 2000. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342: 836-843.
107. Pradhan, A.D., J.E. Manson, N. Rifai, et al. 2001. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286: 327-334.
108. Cook, D.G., M.A. Mendall, P.H. Whincup, et al. 2000. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis 149: 139-150.
109. Ford, E.S., D.A. Galuska, C. Gillespie, et al. 2001. C-reactive protein and body mass index in children: findings from the Third National Health and Nutrition Examination Survey, 1988-1994. J. Pediatr. 138: 486-492.
110. Winer, J.C., T.L. Zern, S.E. Taksali, et al. 2006. Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndrome. J. Clin. Endocrinol. Metab. 91: 4415-4423.
111. Martins, M.D., L. Lima Faleiro & A. Fonseca. 2012. Relationship between leptin and body mass and metabolic syndrome in an adult population. Rev. Port. Cardiol. 31: 711-719.
112. Leyva, F., I.F. Godsland, M. Ghatei, et al. 1998. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler. Thromb. Vasc. Biol. 18: 928-933.
113. Civitarese, A.E. & E. Ravussin. 2008. Mitochondrial energetics and insulin resistance. Endocrinology 149: 950-954.
114. Subasinghe, W., I. Syed & A. Kowluru. 2011. Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic beta-cells: evidence for regulation by Rac1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300: R12-R20.
115. Turrens, J.F. 2003. Mitochondrial formation of reactive oxygen species. J. Physiol. 552: 335-344.
116. 2-induced mitochondrial fragmentation in C2C12 myocytes. Free Radic. Biol. Med. 49: 1646-1654.
117. de Ferranti, S. & D. Mozaffarian. 2008. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin. Chem. 54: 945-955.
118. Bremer, A.A., M.L. Mietus-Snyder & R.H. Lustig. 2012. Toward a unifying hypothesis of metabolic syndrome. Pediatrics 129: 557-570.
119. Schrader, M. & H.D. Fahimi. 2006. Peroxisomes and oxidative stress. Biochim. Biophys. Acta. 1763: 1755-1766.
120. Dirkx, R., I. Vanhorebeek, K. Martens, et al. 2005. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology 41: 868-878.
121. Kapoor, A. & A.J. Sanyal. 2009. Endoplasmic reticulum stress and the unfolded protein response. Clin. Liver Dis. 13: 581-590.
122. Merksamer, P.I., A. Trusina & F.R. Papa. 2008. Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions. Cell 135: 933-947.
123. Haynes, C.M., E.A. Titus & A.A. Cooper. 2004. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol. Cell 15: 767-776.
124. Santos, C.X., L.Y. Tanaka, J. Wosniak & F.R. Laurindo. 2009. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid. Redox Signal 11: 2409-2427.
125. Mollica, M.P., L. Lionetti, R. Putti, et al. 2011. From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation. Nutr. Metab. Cardiovasc. Dis. 21: 222-230.
126. Hummasti, S. & G.S. Hotamisligil. 2010. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Circ. Res. 107: 579-591.
127. Lusis, A.J., A.D. Attie & K. Reue. 2008. Metabolic syndrome: from epidemiology to systems biology. Nat. Rev. Genet. 9: 819-830.
128. Keith, S.W., D.T. Redden, P.T. Katzmaryk, et al. 2006. Putative contributors to the secular increase in obesity: exploring the roads less traveled. Int. J. Obes. 30: 1585-1594.
129. Andrew, R., C.R. Gale, B.R. Walker, et al. 2002. Glucocorticoid metabolism and the metabolic syndrome: associations in an elderly cohort. Exp. Clin. Endocrinol. Diab. 110: 284-290.
130. Kotelevtsev, Y.V., M.C. Holmes, A. Burchell, et al. 1997. 11β-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress. Proc. Nat. Acad. Sci. 94: 14924-14929.
131. Masuzaki, H., J. Paterson, H. Shinyama, et al. 2001. A transgenic model of visceral obesity and the metabolic syndrome. Science 294: 2166-2170.
132. Chandola, T., E. Brunner & M. Marmot. 2006. Chronic stress at work and the metabolic syndrome: prospective study. Br Med J 332: 521-525.
133. Rosengren, A., S. Hawken, S. Ounpuu, et al. 2004. Association of psychosocial risk factors with risk of acute myocardial infarction in 11, 119 cases and 13, 648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 364: 953-962.
134. Brunner, E.J., H. Hemingway, B.R. Walker, et al. 2002. Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study. Circulation 106: 2659-2665.
135. Souverein, P.C., A. Berard, T.P. Van Staa, et al. 2004. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 90: 859-865.
136. Bujalska, I.J., S. Kumar & P.M. Stewart. 1997. Does central obesity reflect "Cushing's disease of the omentum" Lancet 349: 1210-1213.
137. Spiegel, K., J.F. Sheridan & E. Van Cauter. 2002. Effect of sleep deprivation on response to immunization. JAMA 288: 1471-1472.
138. Gangwisch, J.E., D. Malaspina, B. Boden-Albala & S.B. Heymsfield. 2005. Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep 28: 1217-1220.
139. Hasler, G., D.J. Buysse, R. Klaghofer, et al. 2004. The association between short sleep duration and obesity in young adults: a 13-year prospective study. Sleep 27: 602-603.
140. Taheri, S. 2006. The link between short sleep duration and obesity: we should recommend more sleep to prevent obesity. Arch. Dis. Child. 91: 881-884.
141. Sekine, M., T. Yamagami, S. Hamanishi, et al. 2002. Parental obesity, lifestyle factors and obesity in preschool children: results of the Toyama birth cohort study. J. Epidemiol. 12: 33-39.
142. Reilly, J.J., J. Armstrong, A.R. Dorosty, et al. 2005. Early life risk factors for obesity in childhood: cohort study. Br. Med. J. 330: 1357.
143. Waters, K.A., B.T. Mast, S. Vella, et al. 2007. Structural equation modeling of sleep apnea, inflammation, and metabolic dysfunction in children. J. Sleep Res. 16: 388-395.
144. Penev, P.D. 2012. Update on energy homeostasis and insufficient sleep. J. Clin. Endocrinol. Metab. 97: 1792-1801.
145. Parsons, T.J., C. Power, S. Logan & C.D. Summerbell. 1999. Childhood predictors of adult obesity: a systematic review. Int. J. Obes. 23(supp 8): S1-S107.
146. Maffeis, C., Y. Schutz, A. Grezzani, et al. 2001. Meal-induced thermogenesis and obesity: is a fat meal a risk factor for fat gain in children J. Clin. Endocrinol. Metabol. 86: 214-219.
147. Jequier, E. 2001. Is fat intake a risk factor for fat gain in children J. Clin. Endocrinol. Metabol. 86: 980-983.
148. Tucker, L.A., G.T. Seljaas & R.L. Hager. 1997. Body fat percentage of children varies according to their diet composition. J. Am. Dietetic. Assoc. 97: 981-986.
149. Pirozzo, S., C. Summerbell, C. Cameron & P. Glasziou. 2002. Advice on low-fat diets for obesity. Cochrane Database Sys. Rev. CD003640.
150. Kennedy, E. & R. Powell. 1997. Changing eating patterns of American children: a view from 1996. J. Am. Coll. Nutri. 16: 524-529.
151. Harnack, L., J. Stang & M. Story. 1999. Soft drink consumption among US children and adolescents: nutritional consequences. J. Am. Dietetic Assoc. 99: 436-441.
152. Center for Weight and Health. 2001. Pediatric overweight: a review of the literature June 2001: http://www.cnr.berkeley.edu/cwh/news/announcements.shtml-lit_review.
153. Foster, G.D., H.R. Wyatt, J.O. Hill, et al. 2003. A randomized trial of a low-carbohydrate diet for obesity. N. Engl. J. Med. 348: 2082-2090.
154. Stern, L., N. Iqbal, P. Seshadri, et al. 2004. The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann. Int. Med. 140: 778-785.
155. Kirk, S., B. Brehm, B.E. Saelens, et al. 2012. Role of carbohydrate modification in weight management among obese children: a randomized clinical trial. J. Pediatr. 161: 320-327.
156. Vining, E.P., P. Pyzik, J. McGrogan, et al. 2002. Growth of children on the ketogenic diet. Dev. Med. Child. Neurol. 44: 796-802.
157. Gross, L.S., S. Li, E.S. Ford & S. Liu. 2004. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am. J. Clin. Nutr. 79: 774-779.
158. Ludwig, D.S., K.E. Peterson & S.L. Gortmaker. 2001. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet. 357: 505-508.
159. Warner, M.L., K. Harley, A. Bradman, et al. 2006. Soda consumption and overweight status of 2-year-old Mexican-American children in California. Obesity 14: 1966-1974.
160. Faith, M.S., B.A. Dennison, L.S. Edmunds & H.H. Stratton. 2006. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interaction. Pediatrics 118: 2066-2075.
161. Jurgens, H., W. Haass, T.R. Castaneda, et al. 2005. Consuming fructose-sweetened beverages increases body adiposity in mice. Obes. Res. 13: 1146-1156.
162. Bremer, A.A., K.L. Stanhope, J.L. Graham, et al. 2011. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin. Transl. Sci. 4: 243-252.
163. Havel, P.J. 2005. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr. Rev. 63: 133-157.
164. Le, K.A. & L. Tappy. 2006. Metabolic effects of fructose. Curr. Opin. Nutr. Metab. Care 9: 469-475.
165. Lim, J.S., M. Mietus-Snyder, A. Valente, et al. 2010. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat. Rev. Gastroenterol. Hepatol. 7: 251-264.
166. Tuncman, G., J. Hirosumi, G. Solinas, et al. 2006. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl. Acad. Sci. USA. 103: 10741-10746.
167. Stanhope, K.L., J.M. Schwarz, N.L. Keim, et al. 2009. Consuming fructose-, not glucose-sweetened beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 119: 1322-1334.
168. Teff, K.L., J. Grudziak, R.R. Townsend, et al. 2009. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J. Clin. Endocrinol. Metab. 94: 1562-1569.
169. Teff, K.L., S.S. Elliott, M. Tschop, et al. 2004. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J. Clin. Endocrinol. Metab. 89: 2963-2972.
170. Lee, O., W.R. Bruce, Q. Dong, et al. 2009. Fructose and carbonyl metabolites and endogenous toxins. Chem. Biol. Interact. 178: 332-339.
171. Pickens, M.K., J.S. Yan, R.K. Ng, et al. 2009. Dietary sucrose is essential to the development of liver injury in the MCD model of steatohepatitis. J. Lipid Res. 50: 2072-2082.
172. Layman, D.K., D.A. Walker. 2006. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J. Nutr. 136(Suppl): 319S-323S.
173. Newgard, C.B., J. An, J.R. Bain, et al. 2009. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9: 311-326.
174. Higuchi, N., M. Kato, M. Miyazaki, et al. 2011. Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liver. J. Cell. Biochem. 112: 30-38.
175. Eaton, S. 2002. Control of mitochondrial beta-oxidation flux. Prog. Lipid Res. 41: 197-239.
176. Wang, T.J., M.G. Larson, R.S. Vasan, et al. 2011. Metabolic profiles and the risk of developing diabetes. Nat. Med. 17: 448-453.
177. Tai, E.S., M.L. Tan, R.D. Stevens, et al. 2010. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 53: 757-787.
178. Steinberg, D., T.A. Pearson & L.H. Kuller. 1991. Alcohol and atherosclerosis. Ann. Intern. Med. 114: 967-976.
179. Suter, P.M. & Y. Schutz. 2008. The effect of exercise, alcohol or both combined on health and physical performance. Int. J. Obes. 32(suppl. 6): S48-S52.
180. Schneider, J., M. Tesdorfpf, H. Kaffarnik, et al. 1976. Alteration of plasma lipids and intermediates of lipid metabolism in healthy fasting volunteers by ethanol and fructose. Res. Exp. Med. 167: 159-170.
181. Sozio, M. & D.W. Crabb. 2008. Alcohol and lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 295: E10-E16.
182. Yokoyama, H., H. Hiroshi, H. Ohgo, et al. 2007. Effects of excessive ethanol consumption on the diagnosis of the metabolic syndrome using its clinical diagnostic criteria. Intern. Med. 46: 1345-1352.
183. Gupta, N., K. Goel, Bhatt S.P. & Misra A. 2012. Childhood obesity in developing countries: epidemiology, determinants, and prevention. Endocr. Rev. 33: 48-70.
184. Lustig, R.H. & R.Weiss. 2008. Disorders of energy balance. In Textbook of Pediatric Endocrinology. M.A. Sperling, Ed.: 688-713. Elsevier, New York.
185. Lustig, R.H. 2010. Fructose: metabolic, hedonic, and societal parallels with ethanol. J. Am. Diet. Assoc. 110: 1307-1321.