Katarzyna Neubauer
1, Małgorzata Krzystek-Korpacka
2Visfatin/PBEF/Nampt and Other Adipocytokines
in Inflammatory Bowel Disease
Wisfatyna/PBEF/Nampt i inne adipocytokiny
w nieswoistych zapaleniach jelit
1 Department of Gastroenterology and Hepatology, Wroclaw Medical University, Poland 2 Department of Medical Biochemistry, Wroclaw Medical University, Poland
Abstract
Etiopathogenesis of inflammatory bowel disease (IBD), chronic devastating conditions of the gastrointestinal tract, remains unclear. As a consequence, the effective and safe treatment strategy and ideal biochemical disease marker are still missing. IBD are associated with many nutritional problems (cachexia, micro- and macroelements deficien-cies) and additionally there is an abnormal visceral fat structure in Crohn’s disease. Thus, potential involvement of adipocytokines, fat-derivate mediators, in the development of inflammatory bowel disease is extensively studied. List of adipocytokines is growing and currently involves: visfatin/PBEF/Nampt, resistin, adiponectin, apelin, leptin, hepcidin, vaspin, chemerin, omentin, and RBP-4. Adipocytokines possess pleiotropic properties. Visfatin/PBEF/ Nampt acts as a cytokine, growth factor and enzyme. It is suggested that visfatin/PBEF/Nampt participates in the development of inflammation-related bone disease. Elucidation of role of adipocytokines in inflammatory bowel disease requires further studies (Adv Clin Exp Med 2010, 19, 3, 399–404).
Key words: adipocytokines, visfatin/PBEF/Nampt, adiponectine, inflammatory bowel disease.
Streszczenie
Etiopatogeneza nieswoistych zapaleń jelit (n.z.j.), przewlekłych, wyniszczających chorób przewodu pokarmowego pozostaje niejasna. W związku z tym wciąż nie istnieje ani w pełni skuteczna i bezpieczna strategia terapeutycz-na, ani doskonały biochemiczny wskaźnik choroby. Istotnym problemem związanym z n.z.j. są zaburzenia stanu odżywienia (niedożywienie, niedobory mikro- i makroelementów), a w przypadku choroby Leśniowskiego-Crohna zaburzona struktura tkanki tłuszczowej w jamie brzusznej. Dlatego bada się możliwy udział w rozwoju nieswo-istych zapaleń jelit substancji pochodzących z tkanki tłuszczowej, tzw. adipocytokin. Lista adipocytokin stale rośnie i obecnie obejmuje: wisfatynę/PBEF/Nampt, rezystynę, adiponektynę, apelinę, leptynę, hepcydynę, waspinę, omen-tynę, RBP-4. Adipocytokiny mają wielokierunkowe działanie. Wisfatyna/PBEF/Nampt ma właściwości cytokiny, czynnika wzrostu i enzymu. Sugeruje się, że wisfatyna/PBEF/Nampt bierze udział w rozwoju związanej z zapale-niem choroby kości. Wyjaśnienie roli adipocytokin w nieswoistych zapaleniach jelit wymaga dalszych badań (Adv Clin Exp Med 2010, 19, 3, 399–404).
Słowa kluczowe: adipocytokiny, wisfatyna, adiponektyna, nieswoiste zapalenia jelit.
Adv Clin Exp Med 2010, 19, 3, 399–404 ISSN 1230-025X
REVIEWS
© Copyright by Wroclaw Medical University
Inflammatory bowel disease (IBD) are chronic diseases of the digestive tract encompassing ulcer-ative colitis (UC), Crohn’s disease (CD) and in-determinate colitis. Although many studies have been conducted the etiopathogenesis of inflamma-tory bowel disease remains unexplained. Currently accepted hypothesis suggests an involvement of three factors: genetic (especially in CD [1]),
there are still some unresolved problems, espe-cially associated with its safety [3]. Similarly, the golden biochemical marker for disease diagnosis, differential diagnosis, monitoring, prognosis and evaluation of the response for the treatment is not available [4]. Many studies regarding IBD focused on identifying the substance which can poten-tially serve as a therapeutic target or biochemical marker. An interesting, recently studied problem is a role adipocytokines might play in IBD.
Adipocytokines
Recently it was shown that adipose tissue acts as an endocrine organ producing and secreting multifunctional proteins which are termed adipo-cytokines. Adipocytokines take part in the immu-nological, inflammatory, metabolic, and endocrine processes. The list of adipocytokines encompasses inter alia: leptin, adiponectin, resistin, visfatin/
PBEF/Nampt, apelin, hepcidin, vaspin, chemerin, omentin, and RBP-4 and it is still increasing.
Visfatin/PBEF/Nampt
Visfatin/PBEF/Nampt is 52-kDa pleiotropic protein that is highly conserved in evolution. Vis-fatin/PBEF/Nampt was identified in living spe-cies from bacteria to humans. It was shown that visfatin/PBEF/Nampt has properties of cytokine, growth factor and enzyme participating in nico-tinamide adenine dinucleotide metabolism as de-scribed in details below.
Visfatin/PBEF/Nampt was first described by Samal et al. in 1994 as a novel cytokine-like mol-ecule enhancing the effect of stem cell factor (SCF) and IL-7 on pre-B cell colony formation and was termed pre-B cell colony-enhancing factor (PBEF). cDNA encoding PBEF was isolated from activated lymphocytes and characterized [5].
Fukuhara et al. identified in human abdomi-nal visceral fat cDNA fragment corresponding to the 5’-untranslated region of the gene encoding PBEF. In human abdominal visceral fat cDNA, Fukuhara et al. identified fragment corresponding to the 5’-untranslated region of the gene encod-ing PBEF. Moreover, authors found out that the plasma PBEF concentrations are strongly related to the amount of visceral adipose tissue (VAT) but only weakly to subcutaneous fat. Further studies with the mice models of obesity and diabetes led to the conclusion that PBEF is produced abundantly by visceral fat what lead to termed it as visfatin. Moreover, Fukuhara et al. made an attempt to elu-cidate the biological function of visfatin.
Insulin-mimetic function of visfatin, with glucose lower-ing effect was shown, however plasma visfatin concentration, contrary to insulin, did not change upon fasting or feeding in mice [6].
The gene encoding PBEF was found to be a gene encoding human nicotinamide phospho-ribosyltranferase (Nampt). Visfatin/PBEF/Nampt was demonstrated to act as an intra- and extracel-lular NAD biosynthetic enzyme. Nampt-mediated NAD biosynthesis was shown to be critical for β cell function [7].
Although major site of the expression of visfa-tin/PBEF/Nampt is visceral adipose tissue (VAT), this cytokine was also identified in other tissues and organs including brain, kidney, and lungs. Expression of visfatin in chickens (amino acids se-quence of chicken visfatin is 92–93% homologous to mammalian visfatin) was higher in skeletal mus-cle than in visceral adipose tissue, suggesting that visfatin may act as myokine and influence skeletal muscle growth and metabolism [8]. Upregula-tion of visfatin/PBEF/Nampt was demonstrated in inflammation, hypoxia, and hyperglycemia [9]. Both, increases and decreases in circulating visfa-tin/PBEF/Nampt levels as well as changes in its tis-sue expression have been reported in many human diseases and pregnancy [10–12].
Biological function of visfatin/PBEF/Nampt is still not clear. In the study of Chang et al. visfatin/
PBEF/Nampt was not predominatly secreted from VAT and did not correlate with obesity. Visfatin/
PBEF/Nampt mRNA level did not differ between VAT and SAT (subcutaneous adipose tissue) but strongly correlated with pro-inflammatory gene expression (together with TNFα) in VAT and SAT. Author proposed that visfatin/PBEF/Nampt acts as pro-inflammatory marker of adipose tissue associated with systemic insulin resistance and hy-perlipidemia [13].
Conflicting results of the studies on circulat-ing visfatin/PBEF/Nampt may be partly explained by the limitations of the different immunoassays. This observation needs to be included in the in-terpretation of the results of the studies and shows that the crucial role for the understanding of vis-fatin/PBEF/Nampt biology will have development of the reliable immunoassays [14].
Visfatin/PBEF/Nampt
in Metabolic Disorders
higher in patients with diabetes. However, adipo-nectin concentration was decreased and resistin concentration did not differ between patients and control group. Authors suggest that visfatin/PBEF/ Nampt may play a role in the type 2 diabetes patho-genesis [15]. Samara et al. demonstrated a negative correlation of visfatin/PBEF/Nampt expression in the peripheral blood mononuclear cells (PBMCs) with BMI as well as positive linear association of visfatin/PBEF/Nampt expression with TNF-α ex-pression. Authors concluded that visfatin/PBEF/ Nampt may participate in a low-grade inflamma-tion probably existing in obesity, however further studies are needed [16]. Berndt et al. found posi-tive correlation between plasma visfatin/PBEF/ Nampt concentration and visceral visfatin/PBEF/ Nampt mRNA expression with measures of obe-sity (BMI, percent body fat). However, there was no correlation with visceral fat mass calculated from computed tomography scans, waist-to-hip ratio or parameters of insulin sensivity [17]. It is also suggested that visfatin/PBEF/Nampt, together with adiponectin, play a role in the development of insulin resistance mediated by TNFα [18].
Visfatin/PBEF/Nampt
in Rheumatoid Arthritis
Brentano et al. shown that visfatin/PBEF/ Nampt is a pro-inflammatory mediator in rheu-matoid arthritis (RA), the disease which resembles IBD not only because of the chronic inflamma-tory nature but also because of the involvement of TNFα, being key inflammatory cytokine in both diseases. Authors demonstrated that TLR, IL-1β and TNFα are involved in the induction of visfatin in RA synovial fluid. Additionally, the correlation of visfatin level with the severity of inflammation was shown. In conclusion visfatin was suggested as a potential therapeutic target in RA [19].Adipocytokines
in Inflammatory Bowel
Disease
The role of adipocytokines in inflammatory bowel disease requires further elucidation.
Possible involvement of adipocytokines, fat-derivated factors, in the pathogenesis and course of IBD may be hypothesized basing on the well known IBD-associated phenomena:
1. As reviewed by O’Sullivan and O’Morain [20], disease related malnutrition, weight loss and sub-optimal nutritional status are common
findings in patients with both ulcerative colitis and Crohn’s disease.
2. Typical feature of Crohn’s disease is “creeping fat” related to the hypertrophy and wrapping of visceral fat around the small and large bow-el [21].
3. Disturbances of immunological and inflam-matory processes are well documented in in-flammatory bowel disease. Adipocytokines have pro-inflammatory and anti-inflamma-tory properties and additionally participate in immunological phenomena.
4. Changes in local expression and serum level of adipocytokines were shown in patients with inflammatory bowel disease.
Interesting theory regarding the involvement of adipocytokines in the pathogenesis of Crohn’s disease was presented by Batra et al. Authors based on the finding, that in mice with ATG16L1 defi-ciency (mutation of the gene was found in CD) there is an altered production of adipocytokines likewise in mesenteric adipose tissue in CD. Ac-cording to the suggested model, genetic predis-position causes an altered adipocytokine and cy-tokine production in the mesenteric fat. It results in an increased infiltration of immune cells into the lamina propria and increased local cytokine production. This, in turn, stimulates adipocyto-kine release in the adipose tissue. Further con-sequences of above mentioned disturbances are: inappropriate immune response to still unknown environmental factors, increase in adipocytokine production by mesenteric fat due to local immune regulators and bacterial translocation, and hyper-trophy of the mesenteric fat [22].
Gambero et al. determined adipocytokine re-lease by mesenteric fat in rats with experimental colitis. The quantities of adiponectin and leptin re-leased from perinodal adipose tissue were higher in colitis rats as compare to control animals. This finding can be explained with the involvement of adipocytokines in control of inflammatory/im-mune response. No difference was found regard-ing mesenteric adipose tissue. Authors highlighted also other, beside different adipocytokine produc-tion profile, differences between mesenteric and perinodal adipose tissue: different cellular size and different levels of PPAR-γ-2 expression and production of pro-inflammatory and anti-inflam-matory cytokines by perinodal adipose tissue and only pro-inflammatory cytokines by mesenteric adipose tissue [23].
ulcer-ative colitis patients and controls. Authors sug-gest that deregulation of adiponectin production in mesenteric adipose tissue may contribute to the Crohn’s disease development [24].
Secretion of pro-inflammatory and anti-inflammatory adipocytokines by creeping fat in Crohn’s disease was also shown in the study of Paul et al. [25]
Increased serum level of adiponectin, resistin and ghrelin and decreased serum level of leptin was found in patients with UC and CD. However, there was no correlation between serum levels of the adipocytokines and indices of IBD activity (C-reactive protein (CRP), Crohn’s Diseases Activity Index, simple clinical colitis activity index) [26]. Konrad et al. showed elevated resistin levels and significant association of resistin level with elevat-ed white blood cell count, CRP, and disease activ-ity in patients with IBD. Moreover, resistin levels were demonstrated to be an independent predic-tor of disease activity in patients with CD [27].
The possible usefulness of adipocytokines as laboratory markers in clinical practice needs to be evaluated as there is still a need for new laboratory markers in IBD, which can support diagnosis and differential diagnosis, evaluate effectiveness of new therapeutic strategies, or assess activity and prog-nosis of disease [Vermeire et al.].
Results of study of Weigert et al. support the involvement of adipokines in the IBD pathogen-esis. Elevated levels of chemerin and adiponectin were found in patients with IBD, however, there were differences between UC and CD and between genders [28].
Karmiris et al. studied the influence of anti-TNF-α therapy (infliximab) in IBD on the circu-lating levels of selected adipocytokines. Authors suggested that the level of resistin, which was sig-nificantly decreased after biological therapy can serve as a possible marker of successful treatment. However, there was no significant correlation be-tween other studied parameters (changes of BMI, CRP, clinical indices of activity) and alterations of leptin, adiponectin, and resistin [29].
Visfatin/PBEF/Nampt
in Inflammatory Bowel
Diseases
Moschen et al. suggested that visfatin/PBEF/ Nampt may play a role in the pathogenesis of in-flammatory bowel diseases. Authors demonstrat-ed pro-inflammatory properties of visfatin PBEF/
Nampt. The up-regulation of the production of pro- and anti-inflammatory cytokines (IL-1β, IL-1Ra, IL-6, IL-10, TNF-α) in human monocytes medi-ated by visfatin PBEF/Nampt was shown [30].
Recently, Valentini et al. demonstrated elevat-ed level of circulating resistin and visfatin PBEF/ Nampt in patients with active inflammatory bow-el disease, both Crohn’s disease and ulcerative colitis, but not in patients in remission. Level of leptin did not differ, level of adiponectin was de-creased whereas level of retinol-binding protein-4 was increased in patients with active and not ac-tive IBD when compared to the control group. Moreover, authors demonstrated existence of hy-perinsulinemia in about 60% of patients, which was an independent protective factor for mainte-nance of remission. Authors concluded that the results of study highlight the importance of the metabolic-inflammatory response as a modulator in IBD [31].
Involvement of visfatin/PBEF/Nampt in the development of some complications of inflamma-tory bowel diseases is also considered.
Osteopenia and osteoporosis are important complications of IBD, especially of Crohn’s dis-ease. Complex background of those complica-tions includes: nutritional factors (malnutrition, calcium, and vitamin D deficiency), medications (glicocortocisteroids), and chronic inflammation [32]. Bone loss in chronic inflammation is medi-ated by pro-inflammatory agents e.g. TN-α and Il-1. Moschen et al. demonstrated positive cor-relation of serum level of visfatin/PBEF/Nampt with disease activity and negative correlation with bone mineral density in patients with inflamma-tory bowel disease. Additionally, studies in vitro conducted by these authors, have shown that vis-fatin/PBEF/Nampt suppresses osteoclastogenesis. Authors suggested that visfatin PBEF/Nampt may play a role in the development of inflammation-related bone disease [33].
Conclusions
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Address for correspondence:
Katarzyna Neubauer
Department of Gastroenterology and Hepatology Wroclaw Medical University
Borowska 213 50-556 Wrocław Poland
Conflict of interest: None declared
