Horm Metab Res 2013; 45(13): 1009-1019
DOI: 10.1055/s-0033-1358690
Review
© Georg Thieme Verlag KG Stuttgart · New York

Inflammation in Adipose Tissue and Fatty Acid Anabolism: When Enough is Enough!

F. J. Ortega
1   Department of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomédica de Girona (IdIBGi), Girona, Spain
2   CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03) and Instituto de Salud Carlos III (ISCIII), Santiago de Compostela, Spain
,
J. M. Fernández-Real
1   Department of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomédica de Girona (IdIBGi), Girona, Spain
2   CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn, CB06/03) and Instituto de Salud Carlos III (ISCIII), Santiago de Compostela, Spain
› Author Affiliations
Further Information

Publication History

received 30 April 2013

accepted 07 October 2013

Publication Date:
25 November 2013 (online)

Abstract

Recent findings in adipose tissue (AT) have uncovered negative interactions among obesity, lipogenesis, and fatty acid (FA) storage, perhaps in response to the increased production of proinflammatory cytokines and transcription factors. Emerging evidence highlights that local hypoxia, generation of reactive oxygen and nitrogen species, increased immune cells infiltration and activation, senescence, inflammation, energy consumption, and decreased lipogenesis in the AT are interrelated and may lead to impaired cytokine and hormonal secretion by adipocytes, and ectopic fat deposition in obesity that strengths the increased risk of suffering metabolic disorders in obese subjects. The information summarized in this review attempts to defend the interdependent relationship of these proofs of concept, supporting the idea that “inflamed” and “dysfunctional” AT are synonymous when referring to obesity. This may happen in severe obese subjects with a large and long-lasting fat excess, when fat depots have reached the point in which excessive fat storage, cell density, and diminished oxygen availability promote decreased lipo/adipogenesis and increased lipolysis and FA release. This response may be induced by an important inflammatory component that promotes angiogenesis and insulin resistance, but also by leptin and the increase of T3 in hyperplastic AT.

 
  • References

  • 1 Perez-Perez R, Ortega-Delgado FJ, Garcia-Santos E, Lopez JA, Camafeita E, Ricart W, Fernandez-Real JM, Peral B. Differential proteomics of omental and subcutaneous adipose tissue reflects their unalike biochemical and metabolic properties. J Proteome Res 2009; 8: 1682-1693
  • 2 Weiss R. Fat distribution and storage: how much, where, and how?. Eur J Endocrinol 2007; 157 (Suppl. 01) S39-S45
  • 3 Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93: 359-404
  • 4 Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, Vasan RS, Murabito JM, Meigs JB, Cupples LA, D’Agostino Sr RB, O’Donnell CJ. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007; 116: 39-48
  • 5 Arner P. Insulin resistance in type 2 diabetes: role of fatty acids. Diabetes Metab Res Rev 2002; 18 (Suppl. 02) S5-S9
  • 6 Patel P, Abate N. Role of subcutaneous adipose tissue in the pathogenesis of insulin resistance. J Obes 2013; 2013: 489187
  • 7 Mobbs CV, Makimura H. Block the FAS, lose the fat. Nat Med 2002; 8: 335-336
  • 8 Nishimura S, Manabe I, Nagasaki M, Hosoya Y, Yamashita H, Fujita H, Ohsugi M, Tobe K, Kadowaki T, Nagai R, Sugiura S. Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels. Diabetes 2007; 56: 1517-1526
  • 9 Fajas L. Adipogenesis: a cross-talk between cell proliferation and cell differentiation. Ann Med 2003; 35: 79-85
  • 10 Hillgartner FB, Salati LM, Goodridge AG. Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Physiol Rev 1995; 75: 47-76
  • 11 Towle HC, Kaytor EN, Shih HM. Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu Rev Nutr 1997; 17: 405-433
  • 12 Giorgino F, Laviola L, Eriksson JW. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiol Scand 2005; 183: 13-30
  • 13 Wang Y, Jones Voy B, Urs S, Kim S, Soltani-Bejnood M, Quigley N, Heo YR, Standridge M, Andersen B, Dhar M, Joshi R, Wortman P, Taylor JW, Chun J, Leuze M, Claycombe K, Saxton AM, Moustaid-Moussa N. The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue. J Nutr 2004; 134: 1032-1038
  • 14 Claycombe KJ, Jones BH, Standridge MK, Guo Y, Chun JT, Taylor JW, Moustaid-Moussa N. Insulin increases fatty acid synthase gene transcription in human adipocytes. Am J Physiol 1998; 274: R1253-R1259
  • 15 Maier T, Jenni S, Ban N. Architecture of mammalian fatty acid synthase at 4.5 A resolution. Science 2006; 311: 1258-1262
  • 16 Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty Acid Synthase: Association with Insulin Resistance, Type 2 Diabetes, and Cancer. Clin Chem 2009; 55: 425-438
  • 17 Berndt J, Kovacs P, Ruschke K, Kloting N, Fasshauer M, Schon MR, Korner A, Stumvoll M, Bluher M. Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes. Diabetologia 2007; 50: 1472-1480
  • 18 Guichard C, Dugail I, Le Liepvre X, Lavau M. Genetic regulation of fatty acid synthetase expression in adipose tissue: overtranscription of the gene in genetically obese rats. J Lipid Res 1992; 33: 679-687
  • 19 Penicaud L, Ferre P, Assimacopoulos-Jeannet F, Perdereau D, Leturque A, Jeanrenaud B, Picon L, Girard J. Increased gene expression of lipogenic enzymes and glucose transporter in white adipose tissue of suckling and weaned obese Zucker rats. Biochem J 1991; 279 (Pt 1) 303-308
  • 20 Haslam DW, James WP. Obesity. Lancet 2005; 366: 1197-1209
  • 21 Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J 2005; 149: 33-45
  • 22 Asterholm IW, Halberg N, Scherer PE. Mouse Models of Lipodystrophy Key reagents for the understanding of the metabolic syndrome. Drug Discov Today Dis Models 2007; 4: 17-24
  • 23 Medina-Gomez G, Vidal-Puig A. Adipose tissue as a therapeutic target in obesity. Endocrinol Nutr 2009; 56: 404-411
  • 24 Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G, Jelicks LA, Mehler MF, Hui DY, Deshaies Y, Shulman GI, Schwartz GJ, Scherer PE. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007; 117: 2621-2637
  • 25 Lowell BB. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999; 99: 239-242
  • 26 Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994; 331: 1188-1193
  • 27 Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochim Biophys Acta 2010; 1801: 338-349
  • 28 Gregor MF, Hotamisligil GS. Inflammatory Mechanisms in Obesity. Annu Rev Immunol 2011; 29: 415-445
  • 29 Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003; 112: 1785-1788
  • 30 Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proc Natl Acad Sci USA 2000; 97: 11371-11376
  • 31 Moreno-Navarrete JM, Botas P, Valdes S, Ortega FJ, Delgado E, Vazquez-Martin A, Bassols J, Pardo G, Ricart W, Menendez JA, Fernandez-Real JM. Val1483Ile in FASN gene is linked to central obesity and insulin sensitivity in adult white men. Obesity (Silver Spring) 2009; 17: 1755-1761
  • 32 Fernandez-Real JM, Izquierdo M, Moreno-Navarrete JM, Gorostiaga E, Ortega F, Martinez C, Idoate F, Ricart W, Ibanez J. Circulating soluble transferrin receptor concentration decreases after exercise-induced improvement of insulin sensitivity in obese individuals. Int J Obes (Lond) 2009; 33: 768-774
  • 33 Rossmeislova L, Malisova L, Kracmerova J, Tencerova M, Kovacova Z, Koc M, Siklova-Vitkova M, Viquerie N, Langin D, Stich V. Weight loss improves the adipogenic capacity of human preadipocytes and modulates their secretory profile. Diabetes 2013; 62: 1990-1995
  • 34 Roberts R, Hodson L, Dennis AL, Neville MJ, Humphreys SM, Harnden KE, Micklem KJ, Frayn KN. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia 2009; 52: 882-890
  • 35 Suganami T, Tanaka M, Ogawa Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr J 2012; 59: 849-857
  • 36 Liu LH, Wang XK, Hu YD, Kang JL, Wang LL, Li S. Effects of a fatty acid synthase inhibitor on adipocyte differentiation of mouse 3T3-L1 cells. Acta Pharmacol Sin 2004; 25: 1052-1057
  • 37 Letexier D, Pinteur C, Large V, Frering V, Beylot M. Comparison of the expression and activity of the lipogenic pathway in human and rat adipose tissue. J Lipid Res 2003; 44: 2127-2134
  • 38 Eissing L, Scherer T, Todter K, Knippschild U, Greve JW, Buurman WA, Pinnschmidt HO, Rensen SS, Wolf AM, Bartelt A, Heeren J, Buettner C, Scheja L. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat Commun 2013; 4: 1528
  • 39 Ferre P, Foufelle F. SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 2007; 68: 72-82
  • 40 Sewter C, Berger D, Considine RV, Medina G, Rochford J, Ciaraldi T, Henry R, Dohm L, Flier JS, O’Rahilly S, Vidal-Puig AJ. Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 2002; 51: 1035-1041
  • 41 Soukas A, Cohen P, Socci ND, Friedman JM. Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev 2000; 14: 963-980
  • 42 Nadler ST, Attie AD. Please pass the chips: genomic insights into obesity and diabetes. J Nutr 2001; 131: 2078-2081
  • 43 Ortega FJ, Mayas D, Moreno-Navarrete JM, Catalan V, Gomez-Ambrosi J, Esteve E, Rodriguez-Hermosa JI, Ruiz B, Ricart W, Peral B, Fruhbeck G, Tinahones FJ, Fernandez-Real JM. The gene expression of the main lipogenic enzymes is downregulated in visceral adipose tissue of obese subjects. Obesity (Silver Spring) 2010; 18: 13-20
  • 44 Doerrler W, Feingold KR, Grunfeld C. Cytokines induce catabolic effects in cultured adipocytes by multiple mechanisms. Cytokine 1994; 6: 478-484
  • 45 Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 2002; 51: 1319-1336
  • 46 Minehira K, Vega N, Vidal H, Acheson K, Tappy L. Effect of carbohydrate overfeeding on whole body macronutrient metabolism and expression of lipogenic enzymes in adipose tissue of lean and overweight humans. Int J Obes Relat Metab Disord 2004; 28: 1291-1298
  • 47 Zhang W, Della-Fera MA, Hartzell DL, Hausman D, Baile CA. Adipose tissue gene expression profiles in ob/ob mice treated with leptin. Life Sci 2008; 83: 35-42
  • 48 Ortega FJ, Moreno-Navarrete JM, Mayas D, Garcia-Santos E, Gomez-Serrano M, Rodriguez-Hermosa JI, Ruiz B, Ricart W, Tinahones FJ, Fruhbeck G, Peral B, Fernandez-Real JM. Breast cancer 1 (BrCa1) may be behind decreased lipogenesis in adipose tissue from obese subjects. PLoS One 2012; 7: e33233
  • 49 Brunet J, Vazquez-Martin A, Colomer R, Grana-Suarez B, Martin-Castillo B, Menendez JA. BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer. Mol Carcinog 2008; 47: 157-163
  • 50 Moreau K, Dizin E, Ray H, Luquain C, Lefai E, Foufelle F, Billaud M, Lenoir GM, Venezia ND. BRCA1 affects lipid synthesis through its interaction with acetyl-CoA carboxylase. J Biol Chem 2006; 281: 3172-3181
  • 51 Bae I, Fan S, Meng Q, Rih JK, Kim HJ, Kang HJ, Xu J, Goldberg ID, Jaiswal AK, Rosen EM. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res 2004; 64: 7893-7909
  • 52 Moreno-Navarrete JM, Ortega FJ, Ricart W, Fernandez-Real JM. Lacto­ferrin increases (172Thr)AMPK phosphorylation and insulin-induced (p473Ser)AKT while impairing adipocyte differentiation. Int J Obes (Lond) 2009; 33: 991-1000
  • 53 Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002; 967: 379-388
  • 54 Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002; 415: 339-343
  • 55 Cohen P, Friedman JM. Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J Nutr 2004; 134: 2455S-2463S
  • 56 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432
  • 57 Aleixandre de Artinano A, Miguel Castro M. Experimental rat models to study the metabolic syndrome. Br J Nutr 2009; 102: 1246-1253
  • 58 Leibel RL. Molecular physiology of weight regulation in mice and humans. Int J Obes (Lond) 2008; 32 (Suppl 7): S98-S108
  • 59 Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398-401
  • 60 Dahlman I, Arner P. Obesity and polymorphisms in genes regulating human adipose tissue. Int J Obes (Lond) 2007; 31: 1629-1641
  • 61 Oppenheimer JH, Schwartz HL, Lane JT, Thompson MP. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest 1991; 87: 125-132
  • 62 Biondi B. Thyroid and obesity: an intriguing relationship. J Clin Endocrinol Metab 2010; 95: 3614-3617
  • 63 Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol 2010; 316: 165-171
  • 64 De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf) 2007; 67: 265-269
  • 65 Bray GA, Fisher DA, Chopra IJ. Relation of thyroid hormones to body-weight. Lancet 1976; 1: 1206-1208
  • 66 Macek Jilkova Z, Pavelka S, Flachs P, Hensler M, Kus V, Kopecky J. Modulation of type I iodothyronine 5′-deiodinase activity in white adipose tissue by nutrition: possible involvement of leptin. Physiol Res 2009; 59: 561-569
  • 67 Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty acid synthase: association with insulin resistance, type 2 diabetes, and cancer. Clin Chem 2009; 55: 425-438
  • 68 Cabanelas A, Lisboa PC, Moura EG, Pazos-Moura CC. Leptin acute modulation of the 5′-deiodinase activities in hypothalamus, pituitary and brown adipose tissue of fed rats. Horm Metab Res 2006; 38: 481-485
  • 69 Waters KM, Miller CW, Ntambi JM. Localization of a negative thyroid hormone-response region in hepatic stearoyl-CoA desaturase gene 1. Biochem Biophys Res Commun 1997; 233: 838-843
  • 70 Biddinger SB, Miyazaki M, Boucher J, Ntambi JM, Kahn CR. Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c. Diabetes 2006; 55: 2032-2041
  • 71 Poulain-Godefroy O, Lecoeur C, Pattou F, Fruhbeck G, Froguel P. Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 2008; 295: R1-R7
  • 72 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901-911
  • 73 Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 19973 177–182
  • 74 Wilkosz S, Ireland G, Khwaja N, Walker M, Butt R, de Giorgio-Miller A, Herrick SE. A comparative study of the structure of human and murine greater omentum. Anat Embryol (Berl) 2005; 209: 251-261
  • 75 Darimont C, Avanti O, Blancher F, Wagniere S, Mansourian R, Zbinden I, Leone-Vautravers P, Fuerholz A, Giusti V, Mace K. Contribution of mesothelial cells in the expression of inflammatory-related factors in omental adipose tissue of obese subjects. Int J Obes (Lond) 2008; 32: 112-120
  • 76 Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 2000; 106: 809-812
  • 77 Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010; 29: 625-634
  • 78 Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008; 453: 807-811
  • 79 McNamee EN, Korns Johnson D, Homann D, Clambey ET. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res 2013; 55: 58-70
  • 80 Lewis JS, Lee JA, Underwood JC, Harris AL, Lewis CE. Macrophage responses to hypoxia: relevance to disease mechanisms. J Leukoc Biol 1999; 66: 889-900
  • 81 Ye J, Gimble JM. Regulation of stem cell differentiation in adipose tissue by chronic inflammation. Clin Exp Pharmacol Physiol 2011; 38: 872-878
  • 82 Olson N, van der Vliet A. Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease. Nitric Oxide 2011; 25: 125-137
  • 83 Taylor CT, Moncada S. Nitric oxide, cytochrome C oxidase, and the cellular response to hypoxia. Arterioscler Thromb Vasc Biol 2010; 30: 643-647
  • 84 Dai Z, Wu Z, Yang Y, Wang J, Satterfield MC, Meininger CJ, Bazer FW, Wu G. Nitric oxide and energy metabolism in mammals. Biofactors 2013; 39: 383-391
  • 85 Elizalde M, Ryden M, van Harmelen V, Eneroth P, Gyllenhammar H, Holm C, Ramel S, Olund A, Arner P, Andersson K. Expression of nitric oxide synthases in subcutaneous adipose tissue of nonobese and obese humans. J Lipid Res 2000; 41: 1244-1251
  • 86 Marchesi C, Ebrahimian T, Angulo O, Paradis P, Schiffrin EL. Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension 2009; 54: 1384-1392
  • 87 Bondia-Pons I, Ryan L, Martinez JA. Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem 2012; 68: 701-711
  • 88 Stefanovic A, Kotur-Stevuljevic J, Spasic S, Bogavac-Stanojevic N, Bujisic N. The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2008; 79: 156-163
  • 89 Krawczyk SA, Haller JF, Ferrante T, Zoeller RA, Corkey BE. Reactive oxygen species facilitate translocation of hormone sensitive lipase to the lipid droplet during lipolysis in human differentiated adipocytes. PLoS One 2012; 7: e34904
  • 90 Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 2005; 19: 136-138
  • 91 Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond) 2006; 30: 400-418
  • 92 Morrow JD. Is oxidant stress a connection between obesity and atherosclerosis?. Arterioscler Thromb Vasc Biol 2003; 23: 368-370
  • 93 Moreno-Navarrete JM, Ortega F, Sabater M, Ricart W, Fernandez-Real JM. Telomere length of subcutaneous adipose tissue cells is shorter in obese and formerly obese subjects. Int J Obes (Lond) 2010; 34: 1345-1348
  • 94 Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009; 15: 1082-1087
  • 95 Ryan KM, Ernst MK, Rice NR, Vousden KH. Role of NF-kappaB in p53-mediated programmed cell death. Nature 2000; 404: 892-897
  • 96 Molchadsky A, Shats I, Goldfinger N, Pevsner-Fischer M, Olson M, Rinon A, Tzahor E, Lozano G, Zipori D, Sarig R, Rotter V. p53 plays a role in mesenchymal differentiation programs, in a cell fate dependent manner. PLoS One 2008; 3: e3707
  • 97 Bazuine M, Stenkula KG, Cam M, Arroyo M, Cushman SW. Guardian of corpulence: a hypothesis on p53 signaling in the fat cell. Clin Lipidol. 20094 231–243
  • 98 Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 2004; 64: 2627-2633
  • 99 Sell H, Eckel J. Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes. Curr Opin Clin Nutr Metab Care 2010; 13: 366-370
  • 100 Panee J. Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. Cytokine 2012; 60: 1-12
  • 101 Christiansen T, Richelsen B, Bruun JM. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond) 2005; 29: 146-150
  • 102 Famulla S, Horrighs A, Cramer A, Sell H, Eckel J. Hypoxia reduces the response of human adipocytes towards TNFalpha resulting in reduced NF-kappaB signaling and MCP-1 secretion. Int J Obes (Lond) 2012; 36: 986-992
  • 103 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
  • 104 Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K. 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
  • 105 Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3: 23-35
  • 106 Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958-969
  • 107 Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 2009; 58: 2574-2582
  • 108 Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 2009; 94: 4619-4623
  • 109 Prieur X, Mok CY, Velagapudi VR, Nunez V, Fuentes L, Montaner D, Ishikawa K, Camacho A, Barbarroja N, O’Rahilly S, Sethi JK, Dopazo J, Oresic M, Ricote M, Vidal-Puig A. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 2011; 60: 797-809
  • 110 Han MS, Jung DY, Morel C, Lakhani SA, Kim JK, Flavell RA, Davis RJ. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 2013; 339: 218-222
  • 111 Anderson EK, Gutierrez DA, Hasty AH. Adipose tissue recruitment of leukocytes. Curr Opin Lipidol 2010; 21: 172-177
  • 112 Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930-939
  • 113 Ghani S, Feuerer M, Doebis C, Lauer U, Loddenkemper C, Huehn J, Hamann A, Syrbe U. T cells as pioneers: antigen-specific T cells condition inflamed sites for high-rate antigen-non-specific effector cell recruitment. Immunology 2009; 128: e870-e880
  • 114 DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci USA 2013; 110: 5133-5138
  • 115 Chatzigeorgiou A, Karalis KP, Bornstein SR, Chavakis T. Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia 2012; 55: 2583-2592
  • 116 Fernandez-Real JM, Pickup JC. Innate immunity, insulin resistance and type 2 diabetes. Diabetologia 2012; 55: 273-278
  • 117 Gubern C, Lopez-Bermejo A, Biarnes J, Vendrell J, Ricart W, Fernandez-Real JM. Natural antibiotics and insulin sensitivity: the role of bactericidal/permeability-increasing protein. Diabetes 2006; 55: 216-224
  • 118 Lopez-Bermejo A, Chico-Julia B, Castro A, Recasens M, Esteve E, Biarnes J, Casamitjana R, Ricart W, Fernandez-Real JM. Alpha defensins 1, 2, and 3: potential roles in dyslipidemia and vascular dysfunction in humans. Arterioscler Thromb Vasc Biol 2007; 27: 1166-1171
  • 119 Moreno-Navarrete JM, Martinez-Barricarte R, Catalan V, Sabater M, Gomez-Ambrosi J, Ortega FJ, Ricart W, Bluher M, Fruhbeck G, Rodriguez de Cordoba S, Fernandez-Real JM. Complement factor H is expressed in adipose tissue in association with insulin resistance. Diabetes 2010; 59: 200-209
  • 120 Moreno-Navarrete JM, Ortega FJ, Bassols J, Castro A, Ricart W, Fernandez-Real JM. Association of circulating lactoferrin concentration and 2 nonsynonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin Chem 2008; 54: 301-309
  • 121 Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, Nanni G, Pomp A, Castagneto M, Ghirlanda G, Rubino F. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012; 366: 1577-1585
  • 122 Moschen AR, Molnar C, Wolf AM, Weiss H, Graziadei I, Kaser S, Ebenbichler CF, Stadlmann S, Moser PL, Tilg H. Effects of weight loss induced by bariatric surgery on hepatic adipocytokine expression. J Hepatol 2009; 51: 765-777
  • 123 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-783
  • 124 Striz I, Trebichavsky I. Calprotectin – a pleiotropic molecule in acute and chronic inflammation. Physiol Res 2004; 53: 245-253
  • 125 Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol 2003; 170: 3233-3242
  • 126 Johne B, Fagerhol MK, Lyberg T, Prydz H, Brandtzaeg P, Naess-Andresen CF, Dale I. Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol 1997; 50: 113-123
  • 127 Mortensen OH, Nielsen AR, Erikstrup C, Plomgaard P, Fischer CP, Krogh-Madsen R, Lindegaard B, Petersen AM, Taudorf S, Pedersen BK. Calprotectin – a novel marker of obesity. PLoS One 2009; 4: e7419
  • 128 Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Rotellar F, Valenti V, Silva C, Gil MJ, Fernandez-Real JM, Salvador J, Fruhbeck G. Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss. Mol Med 2011; 17: 1157-1167
  • 129 Ortega FJ, Mercader JM, Moreno-Navarrete JM, Sabater M, Pueyo N, Valdes S, Ruiz B, Luche E, Naon D, Ricart W, Botas P, Delgado E, Burcelin R, Fruhbeck G, Bosch F, Mingrone G, Zorzano A, Fernandez-Real JM. Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes. J Mol Med (Berl) 2013; 91: 523-534
  • 130 Ortega FJ, Sabater M, Moreno-Navarrete JM, Pueyo N, Botas P, Delgado E, Ricart W, Fruhbeck G, Fernandez-Real JM. Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes. Eur J Endocrinol 2012; 167: 569-578
  • 131 Marenholz I, Heizmann CW, Fritz G. S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 2004; 322: 1111-1122
  • 132 Foell D, Frosch M, Sorg C, Roth J. Phagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation. Clin Chim Acta 2004; 344: 37-51
  • 133 Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, Leboeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE. S100A9 Differentially Modifies Phenotypic States of Neutrophils, Macrophages, and Dendritic Cells: Implications for Atherosclerosis and Adipose Tissue Inflammation. Circulation 2011; 123: 1216-1226
  • 134 Sjoberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol 2009; 30: 83-90
  • 135 Leal Vde O, Mafra D. Adipokines in obesity. Clin Chim Acta 2013; 419: 87-94
  • 136 Bluher M. Clinical relevance of adipokines. Diabetes Metab J 2012; 36: 317-327
  • 137 Bassols J, Ortega FJ, Moreno-Navarrete JM, Peral B, Ricart W, Fernandez-Real JM. Study of the proinflammatory role of human differentiated omental adipocytes. J Cell Biochem 2009; 107: 1107-1117
  • 138 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83
  • 139 Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone?. Diabetes Care 2003; 26: 2442-2450
  • 140 Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001; 86: 3815-3819
  • 141 Moreno-Navarrete JM, Serrano M, Sabater M, Ortega FJ, Serino M, Pueyo N, Luche E, Waget A, Rodriguez-Hermosa JI, Ricart W, Burcelin R, Fernandez-Real JM. Study of lactoferrin gene expression in human and mouse adipose tissue, human preadipocytes and mouse 3T3-L1 fibroblasts. Association with adipogenic and inflammatory markers. J Nutr Biochem 2013; 24: 1266-1275
  • 142 Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005; 62: 2540-2548
  • 144 Moreno-Navarrete JM, Ortega FJ, Bassols J, Ricart W, Fernandez-Real JM. Decreased circulating lactoferrin in insulin resistance and altered glucose tolerance as a possible marker of neutrophil dysfunction in type 2 diabetes. J Clin Endocrinol Metab 2009; 94: 4036-4044
  • 143 Fernandez-Real JM, Garcia-Fuentes E, Moreno-Navarrete JM, Murri-Pierri M, Garrido-Sanchez L, Ricart W, Tinahones F. Fat overload induces changes in circulating lactoferrin that are associated with postprandial lipemia and oxidative stress in severely obese subjects. Obesity (Silver Spring). 2010; 18: 482-488
  • 145 Moreno-Navarrete JM, Ortega F, Sabater M, Ricart W, Fernandez-Real JM. Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes. J Nutr Biochem 2011; 22: 1143-1149
  • 146 Ono T, Murakoshi M, Suzuki N, Iida N, Ohdera M, Iigo M, Yoshida T, Sugiyama K, Nishino H. Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br J Nutr 2010; 104: 1688-1695
  • 147 Sano H, Kuroki Y. The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Mol Immunol 2005; 42: 279-287
  • 148 Sorensen GL, Hjelmborg JB, Kyvik KO, Fenger M, Hoj A, Bendixen C, Sorensen TI, Holmskov U. Genetic and environmental influences of surfactant protein D serum levels. Am J Physiol Lung Cell Mol Physiol 2006; 290: L1010-L1017
  • 149 Ortega FJ, Pueyo N, Moreno-Navarrete JM, Sabater M, Rodriguez-Hermosa JI, Ricart W, Tinahones FJ, Fernández-Real JM. The lung innate immune gene surfactant protein-D is expressed in adipose tissue and linked to obesity status. Int J Obes (Lond) 2013; doi: 10.1038
  • 150 Fernandez-Real JM, Valdes S, Manco M, Chico B, Botas P, Campo A, Casamitjana R, Delgado E, Salvador J, Fruhbeck G, Mingrone G, Ricart W. Surfactant protein d, a marker of lung innate immunity, is positively associated with insulin sensitivity. Diabetes Care 2010; 33: 847-853
  • 151 Stidsen JV, Khorooshi R, Rahbek MK, Kirketerp-Moller KL, Hansen PB, Bie P, Kejling K, Mandrup S, Hawgood S, Nielsen O, Nielsen CH, Owens T, Holmskov U, Sorensen GL. Surfactant protein d deficiency in mice is associated with hyperphagia, altered fat deposition, insulin resistance, and increased basal endotoxemia. PLoS One 2012; 7: e35066