Heterogeneity of white adipose tissue: Molecular basis and clinical implications

Experimental and Molecular Medicine

Volumn 48, Issue 3, 2016, Pages

  Kwok, Kelvin H M ^a,b   Lam, Karen S L ^a,b   Xu, Aimin ^a,b  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

[No Author keywords available]

Indexed keywords

11BETA HYDROXYSTEROID DEHYDROGENASE 1; 11BETA HYDROXYSTEROID DEHYDROGENASE 1 INHIBITOR; C REACTIVE PROTEIN; CHEMOKINE RECEPTOR CCR2; COMPLEMENT COMPONENT C3; ENZYME INHIBITOR; FATTY ACID BINDING PROTEIN; INTERLEUKIN 6; INTERLEUKIN 8; MONOCYTE CHEMOTACTIC PROTEIN 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PRDM16 PROTEIN; TRANSCRIPTION FACTOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; UNCOUPLING PROTEIN 1;

ADIPOGENESIS; ANGIOGENESIS; BROWN ADIPOSE TISSUE; CARDIOMETABOLIC RISK; CYTOKINE RELEASE; DISEASE PREDISPOSITION; ENERGY HOMEOSTASIS; GLYCATION; HEART DISEASE; HOMEOSTASIS; HUMAN; INFLAMMATION; LIPID METABOLISM; LIPID STORAGE; METABOLIC DISORDER; MOLECULAR BIOLOGY; MOLECULAR PATHOLOGY; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; REVIEW; WHITE ADIPOSE TISSUE; ADIPOSE TISSUE; ANATOMY AND HISTOLOGY; ANIMAL; COMPLICATION; ENERGY METABOLISM; MECHANICS; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ADIPOSE TISSUE; ADIPOSE TISSUE, WHITE; ANIMALS; ENERGY METABOLISM; HUMANS; MECHANICAL PHENOMENA; OBESITY;

EID: 84978730694     PISSN: 12263613     EISSN: 20926413     Source Type: Journal    
DOI: 10.1038/emm.2016.5     Document Type: Review

References (139)

1. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-Analysis. JAMA 2013; 309: 71-82.
2. Kitahara CM, Flint AJ, de Gonzalez AB, Bernstein L, Brotzman M, MacInnis RJ, et al. Association between class III obesity (BMI of 40-59 kg m?2) and mortality: a pooled analysis of 20 prospective studies. PLoS Med 2014; 11: e1001673.
3. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89: 2548-2556.
4. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806.
5. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-783.
6. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277-359.
7. Chudek J, Wiêcek A. Adipose tissue, inflammation and endothelial dysfunction. Pharmacol Rep 2006; 58: 81-88.
8. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4: 20-34.
9. Coutinho T, Goel K, Correa de Sa D, Kragelund C, Kanaya AM, Zeller M, et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol 2011; 57: 1877-1886.
10. Sharma RC Quantitation and localization of regional body fat distribution a comparison between magnetic resonance imaging and somatometry. Obes Res 1996 4 167-178.
11. Zamboni M, Armellini F, Milani MP, Todesco T, De Marchi M, Robbi R, et al. Evaluation of regional body fat distribution: comparison between W/H ratio and computed tomography in obese women. J InternMed 1992; 232: 341-347.
12. Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, et al. Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction. Obes Res 2003; 11: 304-310.
13. Wagner DR. Ultrasound as a tool to assess body fat. J Obes 2013; 2013: 280713.
14. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19: 1252-1263.
15. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293: E444-E452.
16. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011; 7: 137-150.
17. Savage DB. Mouse models of inherited lipodystrophy. Dis Model Mech 2009; 2: 554-562.
18. Goldberg IJ. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res 1996; 37: 693-707.
19. Abumrad NA, El-Maghrabi MR, Amri E, Lopez E, Grimaldi P. Cloning of a rat adipocyte membrane protein implicated in binding or transport of longchain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J Biol Chem 1993; 268: 17665-17668.
20. Trigatti BL, Anderson RG, Gerber GE. Identification of caveolin-1 as a fatty acid binding protein. Biochem Biophys Res Commun 1999; 255: 34-39.
21. Glatz JF, van der Vusse GJ. Intracellular transport of lipids. Mol Cell Biochem 1989; 88: 37-44.
22. Schaffer JE, Lodish HF. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 1994; 79: 427-436.
23. Ellis JM, Frahm JL, Li LO, Coleman RA. Acyl-coenzyme A synthetases in metabolic control. Curr Opin Lipidol 2010; 21: 212-217.
24. Yen C-LE, Stone SJ, Koliwad S, Harris C, Farese RV. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 2008; 49: 2283-2301.
25. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, et al. FAT SIGNALS-lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012; 15: 279-291.
26. Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci USA 2010; 107: 18226-18231.
27. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415-445.
28. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K-i, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494-1505.
29. Boden G. Obesity and free fatty acids. Endocrinol Metab Clin North Am 2008; 37: 635-646.
30. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Eng J Med 2014; 371: 1131-1141.
31. Holzer RG, Park E-J, Li N, Tran H, Chen M, Choi C, et al. Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 2011; 147: 173-184.
32. Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-Terminal Kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 2003; 278: 2896-2902.
33. Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S. The metabolically obese, normal-weight individual revisited. Diabetes 1998; 47: 699-713.
34. Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie ME, Messier V, et al. Characterizing the profile of obese patients who are metabolically healthy. Int J Obes (Lond) 2011; 35: 971-981.
35. Fabbrini E, Yoshino J, Yoshino M, Magkos F, Luecking CT, Samovski D, et al. Metabolically normal obese people are protected from adverse effects following weight gain. J Clin Invest 2015; 125: 787.
36. Bray GA, Jablonski KA, Fujimoto WY, Barrett-Connor E, Haffner S, Hanson RL, et al. Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program. Am J Clin Nutr 2008; 87: 1212-1218.
37. Item F, Konrad D. Visceral fat and metabolic inflammation: the portal theory revisited. Obes Rev 2012; 13: 30-39.
38. Rytka JM, Wueest S, Schoenle EJ, Konrad D. The portal theory supported by venous drainage-selective fat transplantation. Diabetes 2011; 60: 56-63.
39. Jensen MD. Is visceral fat involved in the pathogenesis of the metabolic syndrome?. Human model. Obesity 2006; 14: 20S-24S.
40. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest 2004; 113: 1582-1588.
41. Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr 1996; 85: 2-28.
42. Dunnigan M, Cochrane M, Kelly A, Scott J. Familial lipoatrophic diabetes with dominant transmission. QJM 1974; 43: 33-48.
43. Gesta S, Blüher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci USA 2006; 103: 6676-6681.
44. Tchkonia T, Lenburg M, Thomou T, Giorgadze N, Frampton G, Pirtskhalava T, et al. Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns. Am J Physiol Endocrinol Metab 2009; 292: E298-E307.
45. Pinnick KE, Nicholson G, Manolopoulos KN, McQuaid SE, Valet P, Frayn KN, et al. Distinct developmental profile of lower-body adipose tissue defines resistance against obesity-Associated metabolic complications. Diabetes 2014; 63: 3785-3797.
46. Lundgren M, Svensson M, Lindmark S, Renström F, Ruge T, Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and hyperleptinaemia . Diabetologia 2007; 50: 625-633.
47. Tchkonia T, Tchoukalova YD, Giorgadze N, Pirtskhalava T, Karagiannides I, Forse RA, et al. Abundance of two human preadipocyte subtypes with distinct capacities for replication, adipogenesis, and apoptosis varies among fat depots. Am J Physiol Endocrinol Metab 2005; 288: E267-E277.
48. Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, et al. Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 2006; 55: 2571-2578.
49. Veilleux A, Caron-Jobin M, Noël S, Laberge PY, Tchernof A. Visceral adipocyte hypertrophy is associated with dyslipidemia independent of body composition and fat distribution in women. Diabetes 2011; 60: 1504-1511.
50. Arner P, Andersson DP, Thörne A, Wirén M, Hoffstedt J, Näslund E, et al. Variations in the size of the major omentum are primarily determined by fat cell number. The J Clin Endocrinol Metab 2013; 98: E897-E901.
51. Koutsari C, Ali AH, Mundi MS, Jensen MD. Storage of circulating free fatty acid in adipose tissue of postabsorptive humans: quantitative measures and implications for body fat distribution. Diabetes 2011; 60: 2032-2040.
52. Shadid S, Koutsari C, Jensen MD. Direct free fatty acid uptake into human adipocytes in vivo: relation to body fat distribution. Diabetes 2007; 56: 1369-1375.
53. 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.
54. Lundgren M, Burén J, Ruge T, Myrnäs T, Eriksson JW. Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes. J Clin Endocrinol Metab 2013; 89: 2989-2997.
55. Hoffstedt J, Arner P, Hellers G, Lönnqvist F. Variation in adrenergic regulation of lipolysis between omental and subcutaneous adipocytes from obese and non-obese men. J Lipid Res 1997; 38: 795-804.
56. Arner P. Catecholamine-induced lipolysis in obesity. Int J Obes (Lond) 1999; 23: 10-13.
57. Van Harmelen V, Lönnqvist F, Thörne A, Wennlund A, Large V, Reynisdottir S, et al. Noradrenaline-induced lipolysis in isolated mesenteric, omental and subcutaneous adipocytes from obese subjects. Int J Obes (Lond) 1997; 21: 972-979.
58. Dowling HJ, Fried SK, Pi-Sunyer FX. Insulin resistance in adipocytes of obese women: effects of body fat distribution and race. Metabolism 1995; 44: 987-995.
59. Wu X, Hoffstedt J, Deeb W, Singh R, Sedkova N, Zilbering A, et al. Depot-specific variation in protein-Tyrosine phosphatase activities in human omental and subcutaneous adipose tissue: a potential contribution to differential insulin sensitivity. J Clin Endocrinol Metab 2001; 86: 5973-5980.
60. Jové M, Moreno-Navarrete JM, Pamplona R, Ricart W, Portero-Otín M, Manuel Fernández-Real J. Human omental and subcutaneous adipose tissue exhibit specific lipidomic signatures. FASEB J 2013; 28: 1071-1081.
61. Santosa S, Jensen MD. The sexual dimorphism of lipid kinetics in humans. Front Endocrinol (Lausanne) 2015; 6: 103.
62. Lee M-J, Fried SK. Depot-specific biology of adipose tissues: links to fat distribution and metabolic risk. In: Leff T, Granneman JG (eds). Adipose Tissue in Health and Disease. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2010, pp 283-306.
63. Hocking SL, Wu LE, Guilhaus M, Chisholm DJ, James DE. Intrinsic depot-specific differences in the secretome of adipose tissue, preadipocytes, and adipose tissue-derived microvascular endothelial cells. Diabetes 2010; 59: 3008-3016.
64. Dolinková M, Dostálová I, Lacinová Z, Michalský D, Haluzíková D, Mráz M, et al. The endocrine profile of subcutaneous and visceral adipose tissue of obese patients. Mol Cell Endocrinol 2008; 291: 63-70.
65. Samaras K, Botelho NK, Chisholm DJ, Lord RV. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity 2010; 18: 884-889.
66. Alvehus M, Burén J, Sjöström M, Goedecke J, Olsson T. The human visceral fat depot has a unique inflammatory profile. Obesity 2010; 18: 879-883.
67. Xu A, Vanhoutte PM. Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol 2012; 302: H1231-H1240.
68. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784-1792.
69. Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, et al. Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 2011; 52: 480-488.
70. Bashan N, Dorfman K, Tarnovscki T, Harman-Boehm I, Liberty IF, Blüher M, et al. Mitogen-Activated protein kinases, inhibitory-βB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology 2007; 148: 2955-2962.
71. Fernández-Veledo S, Vila-Bedmar R, Nieto-Vazquez I, Lorenzo M. c-Jun N-Terminal kinase 1/2 activation by tumor necrosis factor-β induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by liver X receptor agonists. J Clin Endocrinol Metab 2009; 94: 3583-3593.
72. Yamamoto Y, Gesta S, Lee KY, Tran TT, Saadatirad P, Kahn CR. Adipose depots possess unique developmental gene signatures. Obesity 2010; 18: 872-878.
73. Chau Y-Y, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W, Lee M, et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol 2014; 16: 367-375.
74. Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, et al. LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose-And depot-specific fashion. Cell Metab 2015; 21: 262-272.
75. Palsgaard J, Emanuelli B, Winnay JN, Sumara G, Karsenty G, Kahn CR. Cross-Talk between Insulin and Wnt signaling in preadipocytes: role of wnt co-receptor low density lipoprotein receptor-related protein-5 (LRP5). J Biol Chem 2012; 287: 12016-12026.
76. Kleppe R, Martinez A, Døskeland SO, Haavik J. The 14-3-3 proteins in regulation of cellular metabolism. Semin Cell Dev Biol 2011; 22: 713-719.
77. Lim GE, Albrecht T, Piske M, Sarai K, Lee JT, Ramshaw HS, et al. 14-3-3 [zeta] coordinates adipogenesis of visceral fat. Nat Commun 2015; 6: 7671.
78. Hilton C, Neville M, Karpe F. MicroRNAs in adipose tissue: their role in adipogenesis and obesity. Int J Obes (Lond) 2013; 37: 325-332.
79. Romao JM, Jin W, He M, McAllister T. Altered microRNA expression in bovine subcutaneous and visceral adipose tissues from cattle under different diet. PLoS ONE 2012; 7: e40605.
80. Heneghan H, Miller N, McAnena O, O'Brien T, Kerin M. Differential miRNA expression in omental adipose tissue and in the circulation of obese patients identifies novel metabolic biomarkers. J Clin Endocrinol Metab 2011; 96: E846-E850.
81. Kloting N, Berthold S, Kovacs P, Schon M, Fasshauer M, Ruschke K, et al. MicroRNA expression in human omental and subcutaneous adipose tissue. PLoS ONE 2009; 4: e4699.
82. Wilson RC, Doudna JA. Molecular mechanisms of RNA interference. Annu Rev Biophys 2013; 42: 217-239.
83. Mori MA, Raghavan P, Thomou T, Boucher J, Robida-Stubbs S, Macotela Y, et al. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 2012; 16: 336-347.
84. Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK, et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest 2014; 124: 3339.
85. Joe AWB, Lin Y, Even Y, Vogl AW, Rossi FMV. Depot-specific differences in adipogenic progenitor abundance and proliferative response to highfat diet. Stem Cells 2009; 27: 2563-2570.
86. Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 2013; 19: 1338-1344.
87. Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol 2015; 17: 376-385.
88. Macotela Y, Emanuelli B, Mori MA, Gesta S, Schulz TJ, Tseng YH, et al. Intrinsic differences in adipocyte precursor cells from different white fat depots. Diabetes 2012; 61: 1691-1699.
89. Wamil M, Battle JH, Turban S, Kipari T, Seguret D, de Sousa Peixoto R, et al. Novel fat depot-specific mechanisms underlie resistance to visceral obesity and inflammation in 11?-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 2011; 60: 1158-1167.
90. Konrad D, Rudich A, Schoenle EJ. Improved glucose tolerance in mice receiving intraperitoneal transplantation of normal fat tissue. Diabetologia 2007; 50: 833-839.
91. Hocking SL, Chisholm DJ, James DE. Studies of regional adipose transplantation reveal a unique and beneficial interaction between subcutaneous adipose tissue and the intra-Abdominal compartment. Diabetologia 2008; 51: 900-902.
92. Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab 2008; 7: 410-420.
93. Foster M, Shi H, Softic S, Kohli R, Seeley R, Woods S. Transplantation of non-visceral fat to the visceral cavity improves glucose tolerance in mice: investigation of hepatic lipids and insulin sensitivity. Diabetologia 2011; 54: 2890-2899.
94. Foster MT, Softic S, Caldwell J, Kohli R, deKloet AD, Seeley RJ. Subcutaneous adipose tissue transplantation in diet-induced obese mice attenuates metabolic dysregulation while removal exacerbates it. Physiol Rep 2013; 1: e00015.
95. Foster MT, Shi H, Seeley RJ, Woods SC. Transplantation or removal of intra-Abdominal adipose tissue prevents age-induced glucose insensitivity. Physio Behav 2010; 101: 282-288.
96. Colombo C, Cutson JJ, Yamauchi T, Vinson C, Kadowaki T, Gavrilova O, et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 2002; 51: 2727-2733.
97. Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 2010; 59: 1648-1656.
98. Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the Src?family kinases, Lck and Fyn, influences T?cell activation, differentiation, and tolerance. Immunol Rev 2009; 228: 9-22.
99. Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC. Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1. Cell Metab 2010; 11: 113-124.
100. Lee T-WA, Kwon H, Zong H, Yamada E, Vatish M, Pessin JE, et al. Fyn deficiency promotes a preferential increase in subcutaneous adipose tissue mass and decreased visceral adipose tissue inflammation. Diabetes 2013; 62: 1537-1546.
101. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol 2011; 12: 231-238.
102. Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, et al. Identification of adipose tissue dendritic cells correlated with obesityassociated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 2012; 61: 2238-2247.
103. Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, et al. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med 2015; 21: 610-618.
104. Kim HS, Ullevig SL, Nguyen HN, Vanegas D, Asmis R. Redox regulation of 14-3-3? controls monocyte migration. Arterioscler Thromb Vasc Biol 2014; 34: 1514-1521.
105. BoseDasgupta S, Moes S, Jenoe P, Pieters J. Cytokine-induced macropinocytosis in macrophages is regulated by 14-3-3? through its interaction with serine-phosphorylated coronin 1. FEBS J 2015; 282: 1167-1181.
106. Kusminski CM, Park J, Scherer PE. MitoNEET-mediated effects on browning of white adipose tissue. Nat Commun 2014; 5: 3962.
107. Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med 2012; 18: 1539-1549.
108. Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, et al. Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 2013; 17: 411-422.
109. Priceman SJ, Kujawski M, Shen S, Cherryholmes GA, Lee H, Zhang C, et al. Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc Natl Acad Sci USA 2013; 110: 13079-13084.
110. Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D, Miller CM, et al. Antigen-And cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 2015; 21: 543-557.
111. Asterholm IW, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV, et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20: 103-118.
112. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 2015; 125: 478-486.
113. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007; 6: 38-54.
114. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011; 121: 96.
115. Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 2014; 156: 304-316.
116. Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPAR? agonists induce a white-To-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 2012; 15: 395-404.
117. Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang A-H, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366-376.
118. Nguyen KD, Qiu Y, Cui X, Goh YPS, Mwangi J, David T, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 2011; 480: 104-108.
119. Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 2014; 157: 1292-1308.
120. Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab 2015; 22: 279-290.
121. Denzel MS, Scimia M-C, Zumstein PM, Walsh K, Ruiz-Lozano P, Ranscht B. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest 2010; 120: 4342.
122. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao T-S, Lodish HF. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/ adiponectin. Proc Natl Acad Sci USA 2004; 101: 10308-10313.
123. Kim AY, Park YJ, Pan X, Shin KC, Kwak S-H, Bassas AF, et al. Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. Nat Commun 2015; 6: 7585.
124. Rupnick MA, Panigrahy D, Zhang C-Y, Dallabrida SM, Lowell BB, Langer R, et al. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 2002; 99: 10730-10735.
125. Bruemmer D. Targeting angiogenesis as treatment for obesity. Arterioscler Thromb Vasc Biol 2012; 32: 161-162.
126. Miyazawa-Hoshimoto S, Takahashi K, Bujo H, Hashimoto N, Saito Y. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia 2003; 46: 1483-1488.
127. Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O'Reilly R, et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 1999; 401: 670-677.
128. Cutchins A, Harmon DB, Kirby JL, Doran AC, Oldham SN, Skaflen M, et al. Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion. Arterioscler Thromb Vasc Biol 2012; 32: 317-324.
129. Galani C, Schneider H. Prevention and treatment of obesity with lifestyle interventions: review and meta-Analysis. Int J Public Health 2007; 52: 348-359.
130. Drew BS, Dixon AF, Dixon JB. Obesity management: update on orlistat. Vasc Health Risk Manag 2007; 3: 817-821.
131. Gloy VL, Briel M, Bhatt DL, Kashyap SR, Schauer PR, Mingrone G, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-Analysis of randomised controlled trials. Br Med J 2013; 347: f5934.
132. Benatti F, Solis M, Artioli G, Montag E, Painelli V, Saito F, et al. Liposuction induces a compensatory increase of visceral fat which is effectively counteracted by physical activity: a randomized trial. J Clin Endocrinol Metab 2012; 97: 2388-2395.
133. Festuccia WT, Blanchard P-G, Turcotte V, Laplante M, Sariahmetoglu M, Brindley DN, et al. Depot-specific effects of the PPAR? agonist rosiglitazone on adipose tissue glucose uptake and metabolism. J Lipid Res 2009; 50: 1185-1194.
134. Berthiaume M, Laplante M, Festuccia W, Gélinas Y, Poulin S, Lalonde J, et al. Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11?-hydroxysteroid dehydrogenase type 1. Endocrinology 2007; 148: 2391-2397.
135. Hanssen MJW, Hoeks J, Brans B, van der Lans AAJJ, Schaart G, van den Driessche JJ, et al. Short-Term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 2015; 21: 863-865.
136. Bonet ML, Oliver P, Palou A. Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 2013; 1831: 969-985.
137. Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, et al. Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 2011; 123: 186-194.
138. Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015; 11: 363-371.
139. Brown NK, Zhou Z, Zhang J, Zeng R, Wu J, Eitzman DT, et al. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models. Arterioscler Thromb Vasc Biol 2014; 34: 1621-1630.