Endokrynologia 3 2013-14

 

Prace poglądowe/Reviews

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Adipokines in the pathogenesis of idiopathic inflammatory bowel disease

Rola adipokin w patogenezie nieswoistych zapaleń jelita grubego

Magdalena Olszanecka-Glinianowicz1, Gabriela Handzlik-Orlik2, Bartłomiej Orlik2, Jerzy Chudek3

1Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical University of Silesia, Katowice, Poland
2Student Scientific Association at Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical University of Silesia, Katowice, Poland
3Pathophysiology Unit, Department of Pathophysiology, Medical University of Silesia, Katowice, Poland

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Prof. Magdalena Olszanecka-Glinianowicz M.D., Ph.D., Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical University of Silesia, Medyków St. 18, 40–752 Katowice, Poland, tel./fax: +48 32 252 60 91, e-mail: magols@esculap.pl

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are the two common forms of idiopathic inflammatory bowel disease (IBD). The aetiology and pathogenesis of IBD are not yet known. Genetic predisposition has been suggested as playing a role in the improper immune response to commensal microbiota. The main link of IBD pathogenesis is an intestinal immune system disability after enteric infection, resulting in an uncontrolled and chronic inflammatory state.

Recently, numerous studies have been focused on the role of proinflammatory cytokines as well as hormones of adipose tissue named adipokines in the pathogenesis of IBD. Adipokines have pro- and anti-inflammatory properties and can modulate the immune response. It has been shown that obesity is associated with systemic microinflammation. On the other hand, experimental studies have revealeda link between levels of some adipokines and the severity of inflammation in IBD independent of body mass. The fat deposits called ‘wrapping’ or ‘creeping’ fat envelop the intestine, and adipokines produced by this tissue play an important role in the pathogenesis of IBD.

The aim of this manuscript was to review the current literature concerning the role of adipokines in the pathogenesis of IBD.

(Endokrynol Pol 2013; 64 (3): 226–231)

Key words: leptin, adiponectin, resistin, visfatin, TNF-α, IL-6, Crohn’s disease, ulcerative colitis

Streszczenie

Choroba Crona (CD) i wrzodziejące zapalenie jelit są najczęściej występującymi postaciami nieswoistych zapaleń jelit. Ich etiologiai patogeneza dotychczas nie zostały wyjaśnione. Sugeruje się, że przewlekły stan zapalny jelit jest wynikiem predyspozycji genetycznych i indywidualnej nadmiernej reakcji układu immunologicznego na antygeny fizjologicznej mikroflory jelitowej. Uważa się, że naruszenie równowagi jelitowego układu immunologicznego jest spowodowane infekcją jelitową, która prowadzi do zmian w składzie fizjologicznej mikroflory jelitowej. Bierze się także pod uwagę takie czynniki, jak pochodzenie geograficzne i etniczne oraz styl życia. W ostatnich latach liczne badania oceniały rolę cytokin prozapalnych i hormonów tkanki tłuszczowej nazywanych adipokinami w patogenezie nieswoistych zapaleń jelit. Adipokiny wykazują zarówno pro-, jak i przeciw- zapalne działania i mogą uczestniczyć w regulacji odpowiedzi immunologicznej. Wykazano także, że otyłość wiąże się z przewlekłym układowym stanem zapalnym. Z drugiej strony wyniki badań eksperymentalnych ujawniły związek między stężeniem krążących adipokin a nasileniem procesu zapalnego w jelicie niezależnie od masy ciała. Wydaje się, że istotną rolę w wytwarzaniu adipokin uczestniczących w patogenezie nieswoistego zapalenia jelita odgrywa depozyt tłuszczu zlokalizowany w krezce jelita i bezpośrednio je otaczający.

Celem prezentowanej pracy był przegląd aktualnej literatury dotyczącej roli adipokin w patogenezie nieswoistych zapaleń jelit, takich jak choroba Crona i wrzodziejące zapalenie jelita grubego.

(Endokrynol Pol 2013; 64 (3): 226–231)

Słowa kluczowe: leptyna, adiponektyna, rezystyna, wisfatyna, TNF-α, IL-6, choroba Crona, wrzodziejące zapalenie jelita grubego

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are the two common forms of idiopathic inflammatory bowel disease (IBD). The aetiology and pathogenesis of both IBD forms are not yet known. It has been suggested that chronic inflammation of the bowel is the result of genetic predisposition and improper immune response to gut commensal microbiota [1]. The importance of genetic predisposition in the pathogenesis of IBD is confirmed by the results described in its higher prevalence in Ashkenazi Jews and first-degree relatives of patients diagnosed with IBD [2]. Moreover, at least nine distinct chromosomal regions loci variants related to IBD have been identified [3, 4]. Additionally, the role of lifestyle in the development of IBD has also been shown [5]. However, the main link of IBD pathogenesis seems to be disability of intestinal immune system after enteric infection, resulting in changes of gut commensal microbiota composition as well as an uncontrolled and chronic inflammatory state. So far no specific microorganism involved in the pathogenesis of IBD has been identified. Therefore, it has been hypothesised that disturbed gut microbiota composition rather than a specific pathogen play a role in the pathogenesis of IBD [6]. The additional known factors, modulating immune system activation and affecting the development of IBD, include use of non-steroidal anti-inflammatory drugs [7], smoking [8], and recent appendectomy [9]. It should be emphasised that smoking is a risk factor for CD [10], while in UC it decreases the severity of inflammation [11, 12]. Recently, numerous studies have been focused on the role of proinflammatory cytokines as well as adipose tissue hormones (adipokines) in the pathogenesis of IBD. It has been shown that obesity per se is associated with systemic microinflammation, and disturbed circulating adipokines levels [13, 14]. Additionally, the results of experimental studies revealed a link, independent of body mass, between plasma levels of adipokines and severity of colitis [15]. In rats, increased mesenteric fat deposit has been observed during experimental colitis, despite a reduction of body mass and enhanced release of TNF-α and leptin by mesenteric and perinodal adipose tissue [30]. Thus, the adipokines produced by these fat deposits called ‘wrapping’ or ‘creeping’ fat enveloping the intestine seem to play an important role in the pathogenesis of IBD [15, 16].

This study reviews the literature concerning the role of adipokines in the pathogenesis of IBD such as Crohn’s disease and ulcerative colitis.

Leptin

Leptin is a 16kDa polypeptide hormone produced predominantly by the subcutaneous white adipose tissue (sWAT) [17]. The circulating leptin level is proportional to body mass index (BMI) and fat mass [18]. Leptin is known as a peripheral signal of satiety [9, 19, 20]. Its other biological activities include regulation of hematopoietic, angiogenesis, reproduction and hypothalamic-pituitary-adrenal axis activation [20–23]. Moreover, leptin has proinflammatory properties. Increased circulating leptin level has been observed in infectious and inflammatory diseases [24, 25]. This adipokine stimulates TNF-α and IL-6 production, increases iNOS activity and the secretion of nitric oxide (NO), activates synthesis of leukotriene by monocytes and macrophages, and modulates function of CD4+ T lymphocytes [18, 26]. This suggests that leptin plays an important role in immunity, influencing the function of immune cells by the regulation of cytokine production and polarising T helper cells toward Th1 (long isoform of leptin receptor is expressed on T lymphocytes) [24].

Experimental studies have revealed that leptin modulates intestinal inflammation [27, 28]. It has been shown that leptin-deficient mice are protected from inflammation in some models of IBD [29], whereas, in a rat experimental model of intestinal inflammation, elevated plasma leptin level was observed, regardless of inflammation severity and nutritional status [30]. Overexpression of leptin mRNA in mesenteric visceral adipose tissue (mWAT) has also been found in IBD subjects, [31, 32], contrary to the suppression of leptin secretion by cultured differentiated human adipocytes in chronic inflammatory conditions [32]. The response of colonic cells to inflammation includes leptin release into the gut lumen which exacerbates the epithelial damage and neutrophil infiltration. Therefore, luminal concentrations of leptin are significantly higher in patients with active IBD than in normal colonic luminal fluid [33]. The studies exploring plasma leptin level in IBD have revealed conflicting results. Its levels have been found to be increased [34], unaffected [35], and even decreased [36]. Additionally, infiximab therapy in patients diagnosed with IBD increases circulating leptin level [37]. Larger studies in humans are necessary to clarify the role of leptin in the pathogenesis of IBD.

Potentially, increased circulating leptin, as well as other proinflammatory cytokines, may increase satiety and decrease food intake in IBD subjects, leading to the development of malnutrition. On the other hand, a high leptin level may improve nutrient absorption. It has been shown that leptin may stimulate nutrient absorption by long isoform of its receptor (OB-Rb) localised in brush border or basolateral membrane of enterocytes [38].

An important limitation of the performed studies, and perhaps the cause of conflicting results, is the lack of nutritional status assessment in IBD subjects. Therefore, more detailed studies are necessary to clarify the potential role of leptin in the pathogenesis of IBD.

Adiponectin

Adiponectin is a 244-amino acid protein, produced predominantly by WAT. The monomeric form (30kDa) as well as oligomeric complexes - low molecular weight (LMW) trimers, middle molecular weight (MMW) hexamers, and high molecular weight (HMW) multimers, of adiponectin seem to be secreted only by adipocytes. It has been suggested that HMW is the most important biologically active adiponectin form [39].

Low plasma adiponectin level has been shown in obesity, type 2 diabetes, dyslipidemia and hypertension [40–42], while increased adiponectin levels have been observed in patients with anorexia nervosa and in fasting healthy subjects [43].

Adiponectin has anti-inflammatory properties. It reduces the release of proinflammatory cytokines such as TNF-α and IL-6 and induces secretion of anti-inflammatory factors (IL-10 and IL-1-receptor antagonist), by macrophages and lymphocytes [44, 45]. Moreover, this adipokine inhibits expression of adhesion molecules (vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1 and IL-8) in endothelial cells [46–48]. However, some investigators suggest that the HMV adiponectin and its globular domain have proinflammatory properties and participate in NFκB activation [49]. Furthermore, elevated plasma adiponectin level has been found in autoimmune diseases such as rheumatoid arthritis [50].

The dual role of adiponectin in IBD has also been shown in experimental studies. Adiponectin-knockout mice (APN-KO) were developing much more severe colitis, that was attenuated by supplementation of adiponectin, probably by the inhibition of LPS-induced IL-8 production in intestinal epithelial cells [51]. On the other hand, adiponectin-deficient mice were protected from chemically induced colitis, and the administration of adiponectin restored inflammation by the increase of proinflammatory cytokines production and inhibition of growth factor activity [52].

In humans, tissue concentration of adiponectin in hypertrophic mesenteric adipose tissue and its release were significantly higher in subjects with CD than UC [53]. However, the results of studies assessing the circulating adiponectin level in IBD subjects are inconclusive. Both elevated [36] and decreased [35] adiponectin levels in IBD have been observed. Moreover, a higher adiponectin level in UC and lower in CD in women, but not in men, has been found [54]. Therefore, gender-related differences in adiponectin action in IBD have been suggested. Moreover, some authors have suggested that circulating adiponectin may be a risk factor for the occurrence of glucocorticoid-related side effects in children and adolescents with IBD [55].

To clarify the role of adiponectin in the pathogenesis of IBD, further experimental and clinical studies are necessary, especially concerning the association between plasma adiponectin levels, IBD and nutritional status as well as fat deposits.

Resistin

Resistin is a 12.5-kDa member of the cysteine-rich proteins family, cloned in 2001 as a thiazolidinedione-regulated cytokine expressed in rodent adipose tissue. It was initially described as an adipocyte-derived mediator of hepatic insulin resistance [56]. When translating the role of resistin from animals to humans, the interspecies differences have to be taken into consideration. The main source of circulating resistin in animals and in humans is different. In animals, resistin is mainly produced by visceral adipocytes [57], while in humans it is by mononuclear cells [58]. Human visceral adipose tissue (predominantly macrophages) produces only a small part of circulating resistin [59]. Additionally, mouse and human resistin demonstrates only 64.4% mRNA sequence and 59% amino acids homology [60]. This suggests that the physiological function of resistin is different in animals and humans [61]. Numerous studies have revealed that in humans resistin has proinflammatory properties. This protein activates NF-κB signalling pathway and induces production of IL-6, IL-1β and TNF-α by monocytes [57, 61]. Other potential but little known functions of resistin are regulation of metabolic processes and adipogenesis [62]. The proinflammatory action of resistin has been confirmed by clinical studies that have revealed the increased level of this protein in rheumatoid arthritis and IBD [63-66]. It has also been shown that resistin production in mWAT is significantly greater in CD than in subjects with colon cancer. Additionally, plasma resistin level in CD and UC patients was increased, independently of the disease severity [36]. Additionally, the increased circulating resistin level in subjects with active IBD but not during remission was found [35]. This suggests the role of resistin in the inflammation process in IBD.

Visfatin

Visfatin is an adipokine originally identified in visceral adipose tissue. The structure of visfatin is identical to pre-B-cell colony-enhancing factor (PBEF). An experimental study revealed the insulin-mimetic properties of visfatin. It was shown that in vitro visfatin enhances glucose uptake by adipocytes and myocytes and inhibits glucose release by hepatocytes [47]. We have recently described a higher circulating visfatin level in obese compared to normal weight women [67]. WAT-derived macrophages and stromal vasculature, rather than adipocytes, are the main source of circulating visfatin [68, 69]. It has been suggested that visfatin is a proinflammatory marker of adipose tissue resident macrophages. Numerous studies have confirmed this hypothesis. Density of resident macrophages in adipose tissue in obese subjects has been shown to be increased. Moreover, both plasma visfatin and TNF-α levels increase with BMI, and correlate with each other [70].

Visfatin stimulates production of matrix-metalloproteinase-9 by monocytes and proinflammatory cytokines, such as TNF-α, IL-6 and IL-8 by peripheral blood mononuclear cells [71, 72]. Increased expression of visfatin in peripheral blood mononuclear cells has also been shown in rheumatoid arthritis [64], acute lung injury [73] and psoriasis [74].

Recently elevated plasma visfatin level has also been observed in subjects diagnosed with IBD. In CD subjects, increased circulating visfatin concentration was observed independent of the disease severity, while in UC subjects visfatin level was related to severity of inflammation. The expression of visfatin was localised to macrophages, epithelial and dendritic cells within mucosa membrane of IBD patients [75].

Additionally, visfatin has been found to be a causative factor of decreased bone mass density (BMD) in IBD subjects [76].

Thus, visfatin seems to be a link in the pathogenesis of IBD and may play a role in the development of IBD complications such as secondary osteoporosis.

Interleukin 6 (IL-6)

Interleukin 6 is a cytokine produced by numerous cells, including fibroblasts, monocytes, macrophages, endothelial cells and adipocytes. Adipose tissue, especially visceral fat, is a significant source of circulating IL-6 (30%) [77]. In obese subjects, an increasing, proportional to BMI, circulating IL-6 level has been shown [78–80].

Experimental studies have revealed that IL-6 plays an important role in the development of insulin resistance by the inducing the suppression of cytokine signalling-3 pathway [81] and stimulating C-reactive protein (CRP) production by hepatocytes [82]. Additionally, IL-6 stimulates hematopoiesis, maturation of B-cells, T-cell growth, as well as differentiation of neurons [82].

Increased concentration of IL-6 in samples collected from both peripheral and mesenteric veins in subjects with active CD, but not with UC, has been shown. It has been suggested that peripheral blood mononuclear cells, endothelial cells and fibroblasts are the main source of circulating IL-6 in CD subjects [83]. In other studies, increased IL-6 level and its relation to disease severity in CD subjects has been found [84, 85]. Therefore, potentially, IL-6 could be a useful marker in the differentiation of CD and UC, and clinical monitoring of CD severity [86, 87]. However, contradictory results have also been published, showing that secretion of IL-6 in mesenteric fat tissue did not differ in subjects with CD, colon cancer and diverticulitis [53, 65]. Finally, large clinical trials have not confirmed the usefulness of IL-6 assessment in CD [88]. Therefore, it seems that elevated circulating IL-6 level may reflect systemic chronic inflammation accompanying IBD.

Tumour necrosis factor-alpha (TNF-α)

Tumour necrosis factor-α is a proinflammatory cytokine produced mainly by macrophages, lymphocytes and in low quantities by human adipocytes [89]. TNF-α directly and indirectly participates in the inflammatory process through recruitment and activation of inflammatory cells. TNF-α interferes also with other cytokines in inflammation and induces catabolism [90], by stimulation of lipoprotein lipase activity and insulin resistance development [91].

Taking into account everything described above, the question arises concerning the participation of adipocyte-derived TNF-α in a chronic inflammation disease, such as IBD. Desreumaux et al. [92] revealed especially elevated secretion of TNF-α from mesenteric adipocytes. It has been suggested that TNF-α synthesis by mesentery adipose tissue is causally linked to the specific location of mucosal ulcerations [93]. Moreover, Gambero et al. [16] in experimental colitis observed its increased production in mesenteric, especially by perinodal, adipose tissue, and this may explain high basal mesenteric lipolytic activity. Elevated TNF-α production by intestinal mucosa in CD patients has also been shown [94]. Tumour necrosis factor-α activates endothelial cells, induces chemokines secretion and recruits neutrophils in gut mucosa [95]. In Crohn’s disease, elevated TNF-αlevel increases leptin mRNA expression in adipocytes [96, 97]. Kohut et al. [85] suggested that circulating TNF-α level may be a marker distinguishing patients with and without Crohn’s disease. The important role of TNF-α in the pathogenesis of CD is confirmed by the effectiveness of therapy with anti-TNF-α drugs in this disease [98].

An increased TNF-α level in the plasma, colonic tissue and stool of UC subjects has also been observed [99]. However, no studies have assessed TNF-α production by intestinal mucosa and perinodal mesenteric adipose tissue in UC patients.

Is obesity a risk factor for inflammatory bowel diseases?

Crohn’s disease and ulcerative colitis generally occur more frequently in obese than in normal weight and underweight subjects. Therefore, some researchers have hypothesised that obesity may participate in the pathogenesis of IBD and influence its severity [100, 101]. The data obtained by Mendall et al. [101] revealed a higher frequency of obesity in patients with CD than ulcerative colitis and healthy controls. A correlation between BMI and risk for CD development has also been shown. Further studies have revealed that the activity of CD is more severe in obese than in non-obese subjects [100]. Contradictory data concerning the frequency of obesity in IBD was obtained in a paediatric population. In children newly-diagnosed with IBD, the prevalence of overweight and obesity was higher in UC than CD subjects (30% v. 20%) [102, 103]. However, the association between obesity and severity of the disease (higher rates of IBD-related surgery interventions) was found only in CD children [102].

The results of the few studies published so far, as well as the above described data, suggest that adipokines are the link between obesity and IBD.

Summary

Disturbances in hormonal function of adipose tissue in obesity seem to modulate immune activity and participate in the pathogenesis as well as the course of IBD. However, further studies are necessary to clarify the role of visceral and mesenteric adipose tissue and more precisely describe the links between obesity and IBD development.

References

  1. 1. Heap GA, Van Heel DA. The genetic of chronic inflammatory diseases. Hum Mol Genet 2009; 18: R101–106.
  2. 2. Yang H, McElree C, Roth MP et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993; 34: 517–524.
  3. 3. Fisher SA, Tremelling M, Anderson CA. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 2008; 40: 710–712.
  4. 4. Franke A, Balschun T, Karlsen TH et al. Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 2008; 40: 713–715.
  5. 5. Baumgart CD, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369: 1627–1640.
  6. 6. Linskens RK, Huijsdens XW, Savelkoul PH et al. The bacterial flora in inflammatory bowel disease: current insights in pathogenesis and the influence of antibiotics and probiotics. Scand J Gastroenterol 2001; 234: 29–40.
  7. 7. Bjarnson I, Zanelli G, Smith T et al. Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 1987; 93: 480–489.
  8. 8. Odes HS, Fich A, Reif S et al. Effects of current cigarette smoking on clinical course of Crohn’s disease and ulcerative colitis. Dig Dis Sci 2001; 46: 1717–1721.
  9. 9. Frisch M, Johansen C, Mellemkiear L et al. Appendectomy and subsequent risk of inflammatory bowel diseases. Surgery 2001; 130: 36-43.
  10. 10. Cosnes J, Beaugerie L, Carbonnel F et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology 2001; 120: 1093–1099.
  11. 11. Boyko EJ, Perera DR, Koepsell TD et al. Effects of cigarette smoking on the clinical course of ulcerative colitis. Scand J Gastroenterol 1988; 23: 1147–1152.
  12. 12. Martins Júnior EV, Araúlo IS, Atallah AN et al. Smoking and inflammatory bowel disease: an epidemiological case-control study. Arq Gastroenterol 1996; 33: 74–78.
  13. 13. Olszanecka-Glinianowicz M, Chudek J, Kocełak P et al. Body fat changes and activity of tumor necrosis factor α system — a 5-year follow up study. Metabolism 2011; 60: 531–536.
  14. 14. Olszanecka-Glinianowicz M, Zahorska-Markiewicz B, Janowska J et al. Serum concentrations of nitric oxide, tumor necrosis factor (TNF)-alpha and TNF-soluble receptors in women with overweight and obesity. Metabolism 2004; 53: 1268–1273.
  15. 15. Mattacks CA, Sadler D, Pond CM. The cellular structure and lipid/protein composition of adipose tissue surrounding chronically stimulated lymph nodes in rats. J Anat 2003; 202: 551–561.
  16. 16. Gambero A, Maróstica M, Abdalla Saad MJ et al. Mesenteric adipose tissue alterations resulting from experimental reactivated colitis. Inflamm Bowel Dis 2007; 13: 1357–1364.
  17. 17. Zhang Y, Proenca R, Maffei M et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.
  18. 18. Otero M. Lago R, Lago F et al. Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 2005; 579: 295–301.
  19. 19. Ahima RS, Saper CB, Flier JS et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000; 21: 263–307.
  20. 20. Yu WH, Kimura M, Walczewska A et al. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 1997; 94: 1023–1028.
  21. 21. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62: 413–437.
  22. 22. Ahima RS. Leptin and the neuroendocrinology of fasting. Front Horm Res 2000; 26: 42–56.
  23. 23. Elias CF, Kelly JF, Lee CE et al. Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol 2000; 423: 261–281.
  24. 24. Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 2001; 15: 2565–2571.
  25. 25. Howard JK, Lord GM, Matarese G et al. Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest 1999; 104: 1051–1059
  26. 26. Lord GM, Matarese G, Howard JK et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897–901.
  27. 27. Mykoniatis A, Anton PM, Wlk M et al. Leptin mediates Clostridium difficile toxin A-induced enteritis in mice. Gastroenterology 2003; 124: 683–691.
  28. 28. Sennello JA, Fayad R, Pini M et al. Transplantation of wild-type white adipose tissue normalizes metabolic, immune and inflammatory alterations in leptin-deficient ob/ob mice. Cytokine 2006; 36: 261–266.
  29. 29. Sigmund B, Sennello JA, Jones-Carson J et al. Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Gut 2004; 53: 965–972.
  30. 30. Barbier M, Cherbut C, Aubé AC et al. Elevated plasma leptin concentrations in early stages of experimental intestinal inflammation in rats. Gut 1998; 43: 783–790.
  31. 31. Barbier M, Vidal H, Desreumaux P et al. Overexpression of leptin mRNA in mesenteric adipose tissue in inflammatory bowel diseases. Gastroenterol Clin Biol 2003; 27: 987–991.
  32. 32. Wang B, Trayhurn P. Acute and prolonged effects of TNF-alpha on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflugers Arch 2006; 452: 418–427.
  33. 33. Sitaraman S, Liu X, Charrier L. Colonic leptin: source of a novel proinflammatory cytokine involved in IBD. FASEB J 2004; 18: 696–698.
  34. 34. Tuzun A, Uygun A, Yesilova Z et al. Leptin levels in the acute stage of ulcerative colitis. J Gastroenterol Hepatol 2004; 19: 429–432.
  35. 35. Valentini L, Wirth EK, Schweizer U et al. Circulating adipokines and the protective effects of hyperinsulinemia in inflammatory bowel disease. Nutrition 2009; 25: 172–181.
  36. 36. Karmiris K, Koutroubakis IE, Xidakis C et al. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm. Bowel Dis 2006; 12: 100–105.
  37. 37. Franchimont D, Roland S, Gustot T et al. Impact of infliximab on serum leptin levels in patients with Crohn’s disease. J Clin Endocrinol Metab 2005; 90: 3510–3516.
  38. 38. Barrentxe J, Villaro AC, Guembe L et al. Distribution of the long leptin receptor isoform in brush border, basolateral membrane, and cytoplasm of enterocytes. Gut 2002; 50: 797–802.
  39. 39. Garaulet M, Hernández-Morante JJ, de Heredia FP et al. Adiponectin, the controversial hormone. Public Health Nutr 2007; 10: 1145–1150.
  40. 40. How WS, Cheung BM, Tso AW. Hypoadiponectinemia as a predictor for the development of hypertension: a 5-year prospective study. Hypertension 2007; 49: 1455–1461.
  41. 41. Okamoto Y, Kihara S, Funahashi T et al. Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond) 2006; 110: 267–278.
  42. 42. Nowak Ł, Adamczak M, Więcek A. Blockade of sympathetic nervous system activity by rilmenidine increases plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2005; 18: 1470–1475.
  43. 43. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005; 115: 911–919.
  44. 44. Lago F, Dieguez C, Gómez-Reino J et al. The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev 2007; 18: 313–325.
  45. 45. Toussirot E, Streit G, Wendling D. The contribution of adipose tissue and adipokines to inflammation in joint diseases. Curr Med Chem 2007; 14: 1095–1100.
  46. 46. Ouchi N, Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta 2007; 380: 24–30.
  47. 47. Piestrzeniewicz K, Luczak K, Komorowski J. Obesity and adiponectin in acute myocardial infarction. Cardiol J 2007; 14: 29–36.
  48. 48. Shetty GK, Economides PA, Horton ES et al. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 2004; 27: 2450–2457.
  49. 49. Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology 2007; 148: 5478–5486.
  50. 50. Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol 2008; 121: 326–330.
  51. 51. Nishihara T, Matsuda M, Araki H et al. Effect of adiponectin on murine colitis induced by dextran sulfate sodium. Gastroenterology 2006; 131: 853–861.
  52. 52. Fayad R, Pini M, Sennello JA et al. Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology 2007; 132: 601–614.
  53. 53. Yamamoto K, Kiyohara T, Marayama Y et al. Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn’s disease. Gut 2005; 54: 789–796.
  54. 54. Weigert J, Obermeier F, Neumeier M et al. Circulating levels of chemerin and adiponectin are higher in ulcerative colitis and chemerin is elevated in Crohn’s disease. Inflamm Bowel Dis 2010; 16: 630–637.
  55. 55. Vihinen MK, Kolho KL, Jänne OA et al. Circulating adiponectin asa marker for glucocorticoid-related side effects in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2009; 48: 504–506.
  56. 56. Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–312.
  57. 57. Bokarewa M, Nagaey I, Dahlberg L et al. Resistin, an adipokine with potent proinflammatory properties. J Immunol 2005; 174: 5789–5795.
  58. 58. Patel L, Buckels AC, Kinghorn IJ et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 2003; 300: 472–476.
  59. 59. Savage DB, Sewter CP, Klenk ES et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 2001; 50: 2199–2202.
  60. 60. Grosh S, Singh AK, Aruna B et al. The genomic organization of mouse resistin reveals major differences from the human resistin: functional implications. Gene 2003; 305: 27–34.
  61. 61. Steppan CM, Lazar MA. The current biology of resistin. J Intern Med 2004; 255: 439–447.
  62. 62. Narata GD, Ongari M, Garlaschelli K et al. Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol 2007; 156: 279–284.
  63. 63. Migita K, Maeda Y, Miyashita T et al. The serum levels of resistin in rheumatoid arthritis patients. Clin Exp Rheumatol 2006; 24: 698–701.
  64. 64. Otero M, Lago R, Gomez R et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1198–1201.
  65. 65. Paul G, Schäffler A, Neumeier M et al. Profiling adipocytokine secretion from creeping fat in Crohn’s disease. Inflamm Bowel Dis 2006; 12: 471–477.
  66. 66. Yaturu S, Reddy RD, Rains J, Jain SK. Plasma and urine levels of resistin and adiponectin in chronic kidney disease. Cytokine 2007; 37: 1–5.
  67. 67. Zahorska-Markiewicz B, Olszanecka-Glinianowicz M, Janowska J et al. Serum concentration of visfatin in obese women. Metabolism 2007; 56: 1131–1134.
  68. 68. Curat CA, Wegner V, Sengenés C et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 2006; 49: 744–747.
  69. 69. Varma V, Yao-Borengasser A, Rasouli N et al. Human visfatin expression: relationship to insulin sensitivity, intramyocellular lipids, and inflammation. J Clin Endocrinol Metab 2007; 92: 666–672.
  70. 70. Olszanecka-Glinianowicz M, Kocełak P, Janowska J, Skorupa A, Nylec M, Zahorska-Markiewicz B. Plasma visfatin and tumor necrosis factor-alpha (TNF-α) level in metabolic syndrome. Kardiol Pol 2011; 69: 802–807.
  71. 71. Chang YC, Chang TJ, Lee WJ et al. The relationship of visfatin/pre-B-cell colony-enhancing factor/nicotinamide phosphoribosyltransferase in adipose tissue with inflammation, insulin resistance, and plasma lipids. Metabolism 2010; 59: 93–99.
  72. 72. Dahl TB, Yndestad A, Skjelland M et al. Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 2007; 115: 972–980.
  73. 73. Ye SQ, Simon BA, Maloney JP et al. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 2005; 171: 361–370.
  74. 74. Koczan D, Guthke R, Thiesen HJ et al. Gene expression profiling of peripheral blood mononuclear leukocytes from psoriasis patients identifies new immune regulatory molecules. Eur J Dermatol 2005; 15: 251–257.
  75. 75. Moschen AR, Kaser A, Enrich B et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 2007; 178: 1748–1758.
  76. 76. Moschen AR, Geiger S, Gerner R et al. Pre-B cell colony enhancing factor/NAMPT/visfatin and its role in inflammation-related bone disease. Mutat Res 2010; 690: 95–101.
  77. 77. Fain JN, Madan AK, Hiler ML et al. Comparison of the release of adipokines by adipose tissue, adipose visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145: 2273–2282.
  78. 78. Bastard JP, Maachi M, Van Nhieu JT et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 2002; 87: 2084–2089.
  79. 79. Olszanecka-Glinianowicz M, Zahorska-Markiewicz B, Janowska J et al. Increased concentration of interleukin-6 (IL-6) is related to obesity but not to insulin resistance. Endokrynol Pol 2004; 55: 437–441.
  80. 80. Olszanecka-Glinianowicz M, Zahorska-Markiewicz B, Janowska J et al. The effect of weight loss on serum concetration of interleukine-6 (IL-6) and insulin resistance. Endokrynol Pol 2006; 57: 131–135.
  81. 81. Senn JJ, Klover PJ, Nowak IA et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 2003; 278: 13740–13746.
  82. 82. Kishimoto T. The biology of interleukin-6. Blood 1989; 74: 1–10.
  83. 83. Mahida YR, Kurlac L, Gallagher A et al. High circulating concentrations of interleukin-6 in active Crohn’s disease but not ulcerative colitis. Gut 1991; 32: 1531–1534.
  84. 84. Brown KA, Back SJ, Ruchelli ED et al. Lamina propria and circulating interleukin-6 in newly diagnosed pediatric inflammatory bowel disease patients. Am J Gastroenterol 2002; 97: 2603–2608.
  85. 85. Kohut M, Hartleb M, Hartleb T. Significance of serum concentrations of pro- and anti-inflammatory cytokines in identification of patients with Crohn’s disease. Pol Merkur Lekarski 2010; 29: 169–172.
  86. 86. Holtkamp W, Stollberg T, Reis HE. Serum interleukin-6 is related to disease activity but not disease specificity in inflammatory bowel disease. J Clin Gastroenterol 1995; 20: 123–126.
  87. 87. Niederau C, Backmerhoff F, Schumacher B. Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative colitis. Hepatogastroenterology 1997; 44: 90–107.
  88. 88. Jones J, Loftus EV Jr, Pannacione R et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2008; 6: 1218–1224.
  89. 89. Winkler G, Kiss S, Keszthelyi L et al. Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level. Eur J Endocrinol 2003; 149: 129–135.
  90. 90. Sherry B, Cerami A. Cachectin/tumor necrosis factor exerts endocrine, paracrine, and autocrine control of inflammatory responses. J Cell Biol 1988; 107: 1269–1277.
  91. 91. Olszanecka-Glinianowicz M, Zahorska-Markiewicz B, Żurakowski A et al.The role of tumor necrosis factor (TNF-alpha) in control of metabolism. Wiad Lek 2005; 58: 670–674.
  92. 92. Desreumaux P, Ernst O, Geboes K et al. Inflammatory alterations in mesenteric adipose tissue in Crohn’s disease. Gastroenterology 1999; 117: 73–81.
  93. 93. Peyrin-Biroulet L, Chamaillard M, Gonzalez F et al. Mesenteric fat in Crohn’s disease: a pathogenetic hallmark or an innocent bystander? Gut 2007; 56: 577–583.
  94. 94. Dionne S, Hiscott J, D’Agata I, Duhaime A, Seidmen EG. Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies. Dig Dis Sci 1997; 42: 1557–1566.
  95. 95. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997; 40: 443–448.
  96. 96. Kirchgessner TG, Uysai KT, Wiesbrock SM et al. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest 1997; 100: 2777–2782.
  97. 97. Zumbach MS, Boehme MW, Wahl P et al. Tumor necrosis factor increases serum leptin levels in humans. J Clin Endocrinol Metab 1997; 82: 4080–4082.
  98. 98. Stack WA, Mann SD, Roy AJ et al. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease. Lancet 1997; 349: 521–524.
  99. 99. Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–2476.
  100. 100. Blain A, Cattan S, Beaugerie L et al. Crohn’s disease clinical course and severity in obese patients. Clin Nutr 2002; 21: 51–57.
  101. 101. Mendall MA, Gunasekera AV, John BJ et al. Is obesity a risk factor for Crohn’s disease? Dig Dis Sci 2011; 56: 837–844.
  102. 102. Kugathasan S, Nebel J, Skelton JA et al. Body mass index in children with newly diagnosed inflammatory bowel disease: observation from two multicenter North American inception cohort. J Pediatr 2007; 151: 523–527.
  103. 103. Long MD, Crandall WV, Leibowitz IH et al. Prevalence and epidemiology of overweight and obesity in children with inflammatory bowel disease. Inflamm Bowel Dis 2011; 17: 2162–2168.

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