Brd2 Gene Disruption Causes " Metabolically Healthy" Obesity. Epigenetic and Chromatin-Based Mechanisms that Uncouple Obesity from Type 2 Diabetes

Vitamins and Hormones

Volumn 91, Issue , 2013, Pages 49-75

  Wang, Fangnian ^a   Deeney, Jude T ^b   Denis, Gerald V ^b  

^a IQUUM Inc   (United States)

^b BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bariatric surgery; Bromodomain; Epigenetics; Insulin resistance; Maternal transmission; Obesity; Type 2 diabetes

Indexed keywords

EID: 84873252833     PISSN: 00836729     EISSN: None     Source Type: Book Series    
DOI: 10.1016/B978-0-12-407766-9.00003-1     Document Type: Chapter

References (137)

1. Aguilar-Salinas C.A., García E.G., Robles L., Riaño D., Ruiz-Gomez D.G., García-Ulloa A.C., et al. High adiponectin concentrations are associated with the metabolically healthy obese phenotype. The Journal of Clinical Endocrinology and Metabolism 2008, 93:4075-4079.
2. Alberti K.G., Eckel R.H., Grundy S.M., Zimmet P.Z., Cleeman J.I., Donato K.A., et al. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120:1640-1645.
3. Apovian C.M., Bigornia S., Mott M., Meyers M.R., Ulloor J., Gagua M., et al. Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arteriosclerosis, Thrombosis, and Vascular Biology 2008, 28:1654-1659.
4. Barker D.J. Fetal origins of coronary heart disease. British Medical Journal 1995, 311:171-174.
5. Barker D.J., Osmond C., Golding J., Kuh D., Wadsworth M.E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. British Medical Journal 1989, 298:654-657.
6. Bastard J.P., Maachi M., Lagathu C., Kim M.J., Caron M., Vidal H., et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. European Cytokine Network 2006, 17:4-12.
7. Beck S., Hanson I., Kelly A., Pappin D.J.C., Trowsdale J. A homologue of the Drosophila female sterile homeotic (fsh) gene in the class II region of the human MHC. DNA Sequence 1992, 2:203-210.
8. Belkina A.C., Blanton W., Wang F., Liu H., Denis G.V. Whole body Brd2 deficiency protects obese mice from insulin resistance by creating a low inflammatory environment. Obesity 2010, 18:S58.
9. Belkina A.C., Denis G.V. Obesity genes and insulin resistance. Current Opinion in Endocrinology, Diabetes, and Obesity 2010, 17:472-477.
10. Belkina A.C., Denis G.V. BET domain co-regulators in obesity, inflammation and cancer. Nature Reviews. Cancer 2012, 12:465-477.
11. Belkina A.C., Nikolajczyk B.S., Denis G.V. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair macrophage inflammatory responses. Journal of Immunology 2013, In press.
12. Bernstein B.E., Meissner A., Lander E.S. The mammalian epigenome. Cell 2007, 128:669-681.
13. Bernstein B.E., Mikkelsen T.S., Xie X., Kamal M., Huebert D.J., Cuff J., et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006, 125:315-326.
14. Bhandare R., Schug J., Le Lay J., Fox A., Smirnova O., Liu C., et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Research 2010, 20:428-433.
15. Blüher M. The distinction of metabolically "healthy" from "unhealthy" obese individuals. Current Opinion in Lipidology 2010, 21:38-43.
16. Bonora E., Willeit J., Kiechl S., Oberhollenzer F., Egger G., Bonadonna R., et al. U-shaped and J-shaped relationships between serum insulin and coronary heart disease in the general population. The Bruneck Study. Diabetes Care 1991, 21:221-230.
17. Burkly L.C., Michaelson J.S., Hahm K., Jakubowski A., Zheng T.S. TWEAKing tissue remodeling by a multifunctional cytokine: Role of TWEAK/Fn14 pathway in health and disease. Cytokine 2007, 40:1-16.
18. Cai D., Yuan M., Frantz D.F., Melendez P.A., Hansen L., Lee J., et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature Medicine 2005, 11:183-190.
19. Calori G., Lattuada G., Piemonti L., Garancini M.P., Ragogna F., Villa M., et al. Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: The Cremona Study. Diabetes Care 2011, 34:210-215.
20. Campbell S., Burkly L.C., Gao H., Berman J.W., Su L., Browning B., et al. Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells. The Journal of Immunology 2006, 176:1889-1898.
21. Cancello R., Henegar C., Viguerie N., Taleb S., Poitou C., Rouault C., et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005, 54:2277-2286.
22. Centers for Disease Control and Prevention (CDC) Vital signs: state-specific obesity prevalence among adults - United States, 2009. MMWR Morb Mortal Wkly Rep 2010, 59(30):951-955.
23. Chacón M.R., Richart C., Gómez J.M., Megía A., Vilarrasa N., Fernández-Real J.M., et al. Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. Cytokine 2006, 33:129-137.
24. Chen J.R., Zhang J., Lazarenko O.P., Kang P., Blackburn M.L., Ronis M.J., et al. Inhibition of fetal bone development through epigenetic down-regulation of HoxA10 in obese rats fed high-fat diet. The FASEB Journal 2012, 26:1131-1141.
25. Christou N.V., Look D., MacLean L.D. Weight gain after short- and long-limb gastric bypass in patients followed for longer than 10 years. Annals of Surgery 2006, 244:734-740.
26. Cinti S., Mitchell G., Barbatelli G., Murano I., Ceresi E., Faloia E., et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. Journal of Lipid Research 2005, 46:2347-2355.
27. Cooper W.N., Khulan B., Owens S., Elks C.E., Seidel V., Prentice A.M., et al. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: Results of a pilot randomized controlled trial. The FASEB Journal 2012, 26:1782-1790.
28. Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabetes Care 2007, 30(Suppl. 2):S169-S174.
29. Dabelea D., Hanson R.L., Lindsay R.S., Pettitt D.J., Imperatore G., Gabir M.M., et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: A study of discordant sibships. Diabetes 2000, 49:2208-2211.
30. Dabelea D., Mayer-Davis E.J., Lamichhane A.P., D'Agostino R.B., Liese A.D., Vehik K.S., et al. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: The SEARCH case-control study. Diabetes Care 2008, 31:1422-1426.
31. Dabelea D., Pettitt D.J. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. Journal of Pediatric Endocrinology & Metabolism 2001, 14:1085-1091.
32. Deering T.G., Ogihara T., Trace A.P., Maier B., Mirmira R.G. Methyltransferase Set7/9 maintains transcription and euchromatin structure at islet-enriched genes. Diabetes 2009, 58:185-193.
33. den Hoed M., Ekelund U., Brage S., Grontved A., Zhao J.H., Sharp S.J., et al. Genetic susceptibility to obesity and related traits in childhood and adolescence: Influence of loci identified by genome-wide association studies. Diabetes 2010, 59:2980-2988.
34. Denis G.V. Bromodomain coactivators in cancer, obesity, type 2 diabetes and inflammation. Discovery Medicine 2010, 10:489-499.
35. Denis G.V., Green M.R. A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulator. Genes and Development 1996, 10:261-271.
36. Denis G.V., Nikolajczyk B.N., Schnitzler G.R. An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis. FEBS Letters 2010, 584:3260-3268.
37. Dhalluin C., Carlson J.E., Zeng L., He C., Aggarwal A.K., Zhou M.-M. Structure and ligand of a histone acetyltransferase bromodomain. Nature 1999, 399:491-496.
38. Digan M.E., Haynes S.R., Mozer B.A., Dawid I.B., Forquignon F., Gans M. Genetic and molecular analysis of fs(1)h, a maternal effect homeotic gene in Drosophila. Developmental Biology 1986, 114:161-169.
39. Ditschuneit H.H., Flechtner-Mors M., Johnson T.D., Adler G. Metabolic and weight-loss effects of a long-term dietary intervention in obese patients. The American Journal of Clinical Nutrition 1999, 69:198-204.
40. Duffey K.J., Popkin B.M. High-fructose corn syrup: Is this what's for dinner?. The American Journal of Clinical Nutrition 2008, 88:1722S-1732S.
41. Evans-Molina C., Robbins R.D., Kono T., Tersey S.A., Vestermark G.L., Nunemaker C.S., et al. Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Molecular and Cellular Biology 2009, 29:2053-2067.
42. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Journal of the American Medical Association 2001, 285:2486-2497.
43. Farooqi S., O'Rahilly S. Genetics of obesity in humans. Endocrine Reviews 2006, 27:710-718.
44. Filippakopoulos P., Qi J., Picaud S., Shen Y., Smith W.B., Fedorov O., et al. Selective inhibition of BET bromodomains. Nature 2010, 468:1067-1073.
45. Finucane M.M., Stevens G.A., Cowan M.J., Danaei G., Lin J.K., Paciorek C.J., et al. Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: Systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. The Lancet 2011, 377:557-567.
46. Florez J. The genetics in Type 2 diabetes: A realistic appraisal in 2008. The Journal of Clinical Endocrinology and Metabolism 2008, 93:4633-4642.
47. Francis J., Chakrabarti S.K., Garmey J.C., Mirmira R.G. Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription. The Journal of Biological Chemistry 2005, 280:36244-36253.
48. Frayling T.M., Timpson N.J., Weedon M.N., Zeggini E., Freathy R.M., Lindgren C.M., et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007, 316:889-894.
49. Freund A., Orjalo A.V., Desprez P.Y., Campisi J. Inflammatory networks during cellular senescence: Causes and consequences. Trends in Molecular Medicine 2010, 16:238-246.
50. Grundy S.M., Cleeman J.I., Daniels S.R., Donato K.A., Eckel R.H., Franklin B.A., et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005, 112:2735-2752. Erratum in: Circulation 112, e297, e298 (2005).
51. Hales C.N., Barker D.J., Clark P.M., Cox L.J., Fall C., Osmond C., et al. Fetal and infant growth and impaired glucose tolerance at age 64. British Medical Journal 1991, 303:1019-1022.
52. Haslam D.W., James W.P. Obesity. The Lancet 2009, 366:1197-1209.
53. Haynes S.R., Dollard C., Winston F., Beck S., Trowsdale J., Dawid I.B. The bromodomain: A conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Research 1992, 20:2603.
54. Heerwagen M.J., Miller M.R., Barbour L.A., Friedman J.E. Maternal obesity and fetal metabolic programming: A fertile epigenetic soil. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2010, 299:R711-R722.
55. Horn P.J., Peterson C.L. The bromodomain: A regulator of ATP-dependent chromatin remodeling?. Frontiers in Bioscience 2001, 6:D1019-D1023.
56. Hossain P., Kawar B., El Nahas M. Obesity and diabetes in the developing world-A growing challenge. The New England Journal of Medicine 2007, 356:213-215.
57. Hotamisligil G.S., Shargill N.S., Spiegelman B.M. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 1993, 259:87-91.
58. Jaenisch R., Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nature Genetics 2003, 33(Suppl.):245-254.
59. Jagannathan M., Hasturk H., Liang Y., Shin H., Hetzel J.T., Kantarci A., et al. TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. The Journal of Immunology 2009, 183:7461-7470.
60. Jagannathan M., McDonnell M., Liang Y., Hasturk H., Hetzel J., Rubin D., et al. Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 2010, 53:1461-1471.
61. Jeanmougin F., Wurtz J.-M., Le Douarin B., Chambon P., Losson R. The bromodomain revisited. Trends in Biochemical Sciences 1997, 22:151-153.
62. Kahn S.E., Zinman B., Haffner S.M., O'Neill M.C., Kravitz B.G., Yu D., et al. Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes 2006, 55:2357-2364.
63. Kanno T., Kanno Y., Siegel R.M., Jang M.K., Lenardo M.J., Ozato K. Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Molecular Cell 2004, 13:33-43.
64. Karelis A.D., Faraj M., Bastard J.P., St-Pierre D.H., Brochu M., Prud'homme D., et al. The metabolically healthy but obese individual presents a favorable inflammation profile. The Journal of Clinical Endocrinology and Metabolism 2005, 90:4145-4150.
65. Kern P.A. Potential role of TNFalpha and lipoprotein lipase as candidate genes for obesity. The Journal of Nutrition 1997, 127:1917S-1922S.
66. Kern P.A., Ranganathan S., Li C., Wood L., Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. American Journal of Physiology. Endocrinology and Metabolism 2001, 280:E745-E751.
67. Khan T., Muise E.S., Iyengar P., Wang Z.V., Chandalia M., Abate N., et al. Metabolic dysregulation and adipose tissue fibrosis: Role of collagen VI. Molecular and Cellular Biology 2009, 29:1575-1591.
68. Kim S.J., Nian C., McIntosh C.H. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 modulate beta-cell chromatin structure. The Journal of Biological Chemistry 2009, 284:12896-12904.
69. Kim J.Y., van de Wall E., Laplante M., Azzara A., Trujillo M.E., Hofmann S.M., et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. The Journal of Clinical Investigation 2007, 117:2621-2637.
70. Kintscher U., Hartge M., Hess K., Foryst-Ludwig A., Clemenz M., Wabitsch M., et al. T-lymphocyte infiltration in visceral adipose tissue: A primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology 2008, 28:1304-1310.
71. Klannemark M., Orho M., Langin D., Laurell H., Holm C., Reynisdottir S., et al. The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity. Diabetologia 1998, 41:1516-1522.
72. Klöting N., Fasshauer M., Dietrich A., Kovacs P., Schön M.R., Kern M., et al. Insulin-sensitive obesity. American Journal of Physiology. Endocrinology and Metabolism 2010, 299:E506-E515.
73. Kyle U.G., Pichard C. The Dutch Famine of 1944-1945: A pathophysiological model of long-term consequences of wasting disease. Current Opinion in Clinical Nutrition and Metabolic Care 2006, 9:388-394.
74. Lee K. Metabolically obese but normal weight (MONW) and metabolically healthy but obese (MHO) phenotypes in Koreans: Characteristics and health behaviors. Asia Pacific Journal of Clinical Nutrition 2009, 18:280-284.
75. Lefebvre A.M., Laville M., Vega N., Riou J.P., van Gaal L., Auwerx J., et al. Depot-specific differences in adipose tissue gene expression in lean and obese subjects. Diabetes 1998, 47:98-103.
76. Leibel R.L. Energy in, energy out, and the effects of obesity-related genes. The New England Journal of Medicine 2008, 359:2603-2604.
77. LeRoy G., Rickards B., Flint S.J. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Molecular Cell 2008, 30:51-60.
78. Levin B.E., Govek E. Gestational obesity accentuates obesity in obesity-prone progeny. The American Journal of Physiology 1998, 275:R1374-R1379.
79. Li B., Carey M., Workman J.L. The role of chromatin during transcription. Cell 2007, 128:707-719.
80. Li H., Mittal A., Paul P.K., Kumar M., Srivastava D.S., Tyagi S.C., et al. Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of Nuclear Factor-κB-inducing kinase and p38 mitogen-activated protein kinase. The Journal of Biological Chemistry 2009, 284:4439-4450.
81. Lin Y.J., Umehara T., Inoue M., Saito K., Kigawa T., Jang M.K., et al. Solution structure of the extraterminal domain of the bromodomain-containing protein BRD4. Protein Science 2008, 17:2174-2179.
82. Maes H.H., Neale M.C., Eaves L.J. Genetic and environmental factors in relative body weight and human adiposity. Behavior Genetics 1997, 27:325-351.
83. Magro D.O., Geloneze B., Delfini R., Pareja B.C., Callejas F., Pareja J.C. Long-term weight regain after gastric bypass: A 5-year prospective study. Obesity Surgery 2008, 18:648-651.
84. Mahdi H., Fisher B.A., Källberg H., Plant D., Malmström V., Rönnelid J., et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nature Genetics 2009, 41:1319-1324.
85. Martínez J.A., Cordero P., Campión J., Milagro F.I. Interplay of early-life nutritional programming on obesity, inflammation and epigenetic outcomes. The Proceedings of the Nutrition Society 2012, 71:276-283.
86. Matthews D.R., Hosker J.P., Rudenski A.S., Naylor B.A., Treacher D.F., Turner R.C. Homeostasis model assessment: Insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28:412-419.
87. McDonnell M.E., Ganley-Leal L.M., Mehta A., Bigornia S.J., Mott M., Rehman Q., et al. B lymphocytes in human subcutaneous adipose crown-like structures. Obesity (Silver Spring) 2012, 20:1372-1378.
88. McGillicuddy F.C., Harford K.A., Reynolds C.M., Oliver E., Claessens M., Mills K.H.G., et al. Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes 2011, 60:1688-1698.
89. Meigs J.B., Wilson P.W., Fox C.S., Vasan R.S., Nathan D.M., Sullivan L.M., et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. The Journal of Clinical Endocrinology and Metabolism 2006, 91:2906-2912.
90. Morris B.J., Zee R.Y., Robinson B.G. Significant relationships of plasma lipids and body mass index with polymorphisms at the linked low-density-lipoprotein receptor gene and insulin receptor gene loci (19p13.2) in essential hypertensive patients. Clinical Science (London, England) 1994, 86:583-592.
91. Muller Y., Abdussamad M., Hanson R., Knowler W.C., Bogardus C., Baier L. Variants in/near BRD2 are associated with body mass index in Pima Indians. Diabetes 2011, 60(Suppl. 1):A1400.
92. Muller S., Filippakopoulos P., Knapp S. Bromodomains as therapeutic targets. Expert Reviews in Molecular Medicine 2011, 13:e29.
93. Nakamura Y., Umehara T., Nakano K., Jang M.K., Shirouzu M., Morita S., et al. Crystal structure of the human BRD2 bromodomain: Insights into dimerization and recognition of acetylated histone H4. The Journal of Biological Chemistry 2007, 282:4193-4201.
94. Nathanielsz P.W., Poston L., Taylor P.D. In utero exposure to maternal obesity and diabetes: Animal models that identify and characterize implications for future health. Clinics in Perinatology 2007, 34:515-526.
95. Nicodeme E., Jeffrey K.L., Schaefer U., Beinke S., Dewell S., Chung C.W., et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010, 468:1119-1123.
96. Odegaard J.I., Ricardo-Gonzalez R.R., Goforth M.H., Morel C.R., Subramanian V., Mukundan L., et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 2007, 447:1116-1120.
97. Ohashi K., Parker J.L., Ouchi N., Higuchi A., Vita J.A., Gokce N., et al. Adiponectin promotes macrophage polarization towards an anti-inflammatory phenotype. The Journal of Biological Chemistry 2009, 285:6153-6160.
98. Oppert J.M., Vohl M.C., Chagnon M., Dionne F.T., Cassard-Doulcier A.M., Ricquier D., et al. DNA polymorphism in the uncoupling protein (UCP) gene and human body fat. International Journal of Obesity and Related Metabolic Disorders 1994, 18:526-531.
99. Orjalo A.V., Bhaumik D., Gengler B.K., Scott G.K., Campisi J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proceedings of the National Academy of Science of the United States of America 2009, 106:17031-17036.
100. Pedersen T.A., Kowenz-Leutz E., Leutz A., Nerlov C. Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes and Development 2001, 15:3208-3216.
101. Perreault M., Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nature Medicine 2001, 7:1138-1143.
102. Pickup J.C., Crook M.A. Is type II diabetes mellitus a disease of the innate immune system?. Diabetologia 1998, 41:1241-1248.
103. Popkin B.M. The world is fat. Scientific American 2007, 297:88-95.
104. Popkin B.M., Nielsen S.J. The sweetening of the world's diet. Obesity Research 2003, 11:1325-1332.
105. Puigserver P., Wu Z., Park C.W., Graves R., Wright M., Spiegelman B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92:829-839.
106. Rahman S., Sowa M.E., Ottinger M., Smith J.A., Shi Y., Harper J.W., et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Molecular and Cellular Biology 2011, 31:2641-2652.
107. Ravussin E. Metabolic differences and the development of obesity. Metabolism 1995, 9(Suppl. 3):12-14.
108. Reynisdottir S., Ellerfeldt K., Wahrenberg H., Lithell H., Arner P. Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. The Journal of Clinical Investigation 1994, 93:2590-2599.
109. Ricquier D., Casteilla L., Bouillaud F. Molecular studies of the uncoupling protein. The FASEB Journal 1991, 5:2237-2242.
110. Ridderstråle M., Groop L. Genetic dissection of type 2 diabetes. Molecular and Cellular Endocrinology 2009, 297:10-17.
111. Romano M., Guagnano M.T., Pacini G., Vigneri S., Falco A., Marinopiccoli M., et al. Association of inflammation markers with impaired insulin sensitivity and coagulative activation in obese healthy women. The Journal of Clinical Endocrinology and Metabolism 2003, 88:5321-5326.
112. Saghizadeh M., Ong J.M., Garvey W.T., Henry R.R., Kern P.A. The expression of TNF alpha by human muscle. Relationship to insulin resistance. The Journal of Clinical Investigation 1996, 97:1111-1116.
113. Samuelsson A.M., Matthews P.A., Argenton M., Christie M.R., McConnell J.M., Jansen E.H., et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: A novel murine model of developmental programming. Hypertension 2008, 51:383-392.
114. Sanchez R., Zhou M.-M. The role of human bromodomains in chromatin biology and gene transcription. Current Opinion in Drug Discovery and Development 2009, 12:659-665.
115. Schneck L., Valenti C., Amsterdam D., Friedland J., Adachi M., Volk B.W. Prenatal diagnosis of Tay-Sachs disease. The Lancet 1970, 1:582-584.
116. Shankar K., Harrell A., Liu X., Gilchrist J.M., Ronis M.J., Badger T.M. Maternal obesity at conception programs obesity in the offspring. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2008, 294:R528-R538.
117. Shankar K., Zhong Y., Kang P., Lau F., Blackburn M.L., Chen J.R., et al. Maternal obesity promotes a proinflammatory signature in rat uterus and blastocyst. Endocrinology 2011, 152:4158-4170.
118. Sharma S., Kelly T.K., Jones P.A. Epigenetics in cancer. Carcinogenesis 2010, 31:27-36.
119. Shaw J.E., Sicree R.A., Zimmet P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Research and Clinical Practice 2010, 87:4-14.
120. Shoelson S.E., Herrero L., Naaz A. Obesity, inflammation and insulin resistance. Gastroenterology 2007, 132:2169-2180.
121. Shoelson S.E., Lee J., Goldfine A.B. Inflammation and insulin resistance. The Journal of Clinical Investigation 2006, 116:1793-1801.
122. Silventoinen K., Rokholm B., Kaprio J., Sørensen T.I. The genetic and environmental influences on childhood obesity: A systematic review of twin and adoption studies. International Journal of Obesity 2010, 34:29-40.
123. Sims E.A.H. Are there persons who are obese, but metabolically healthy?. Metabolism 2001, 50:1499-1504.
124. Stich V., Harant I., De Glisezinski I., Crampes F., Berlan M., Kunesova M., et al. Adipose tissue lipolysis and hormone-sensitive lipase expression during very-low-calorie diet in obese female identical twins. The Journal of Clinical Endocrinology and Metabolism 1997, 82:739-744.
125. Succurro E., Marini M.A., Frontoni S., Hribal M.L., Andreozzi F., Lauro R., et al. Insulin secretion in metabolically obese, but normal weight, and in metabolically healthy but obese individuals. Obesity (Silver Spring) 2008, 16:1881-1886.
126. Umehara T., Nakamura Y., Jang M.K., Nakano K., Tanaka A., Ozato K., et al. Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain. The Journal of Biological Chemistry 2010, 285:7610-7618.
127. Uysal K.T., Wiesbrock S.M., Marino M.W., Hotamisligil G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997, 389:610-614.
128. Vidal-Puig A.J., Considine R.V., Jimenez-Liñan M., Werman A., Pories W.J., Caro J.F., et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. The Journal of Clinical Investigation 1997, 99:2416-2422.
129. Walston J., Silver K., Bogardus C., Knowler W.C., Celi F.S., Austin S., et al. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. The New England Journal of Medicine 1995, 333:343-347.
130. Wang F., Liu H., Blanton W.P., Belkina A., LeBrasseur N.K., Denis G.V. Brd2 disruption in mice causes severe obesity without type 2 diabetes. The Biochemical Journal 2009, 425:71-83.
131. Waterland R.A., Travisano M., Tahiliani K.G., Rached M.T., Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. International Journal of Obesity 2008, 32:1373-1379.
132. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation 2003, 112:1796-1808.
133. Wild S., Roglic G., Green A., Sicree R., King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27:1047-1053.
134. Wildman R.P., Muntner P., Reynolds K., McGinn A.P., Rajpathak S., Wylie-Rosett J., et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: Prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Archives of Internal Medicine 2008, 168:1617-1624.
135. Winston F., Allis C.D. The bromodomain: A chromatin-targeting module?. Nature Structural Biology 1999, 6:601-604.
136. Xu H., Barnes G.T., Yang Q., Tan G., Yang D., Chou C.J., et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of Clinical Investigation 2003, 112:1821-1830.
137. Zhao J., Bradfield J.P., Li M., Wang K., Zhang H., Kim C.E., et al. The role of obesity-associated loci identified in genome-wide association studies in the determination of pediatric BMI. Obesity (Silver Spring) 2009, 17:2254-2257.