leptin and Crohn-Disease

The differential diagnosis of inflammatory bowel diseases (IBDs) between Crohn's disease (CD) and ulcerative colitis (UC) is important for designing an effective therapeutic regimen. However, without any adequate gold standard method for differential diagnosis currently, therapeutic design remains a major challenge in clinical practice. In this context, recent studies have showed that circulating leptin stands out as a potential biomarker for the categorization of IBDs. Thus, we aimed to summarize the current understanding of the prognostic and diagnostic value of serum leptin in patients with IBDs.. A systematic search was performed in PubMed/MEDLINE, Scopus, Cochrane Library, and Web of Science databases. Articles that aimed to study the relationship between circulating levels of leptin and IBDs were included. Finally, the meta-analysis was performed with the mean serum leptin levels in patients with IBDs and healthy controls using RevMan 5.3 software, with I2 > 50% as a criterion for substantial heterogeneity.. Nineteen studies were included. Serum leptin levels among patients with IBDs and healthy controls did not show a significant difference (95% CI, -2.15 to 0.57; I2, 86%, P ≤ 0.00001). Similarly, there was no association of leptin levels with the activity of IBDs (95% CI, -0.24 to 0.06; I2, 50%; P = 0.13). However, serum leptin levels were significantly higher in patients with CD than those in patients with UC (95% CI, -2.09 to -0.37; I2, 7%; P ≤ 0.36).. This review suggested that serum leptin levels might be a promising biomarker to help in the differentiation between CD and UC.

Topics: Biomarkers; Colitis, Ulcerative; Crohn Disease; Humans; Leptin

In just over a generation overweight and obesity has become a worldwide health concern. The ramifications for this on future health care costs and longevity are consequent, whilst increased adiposity is a harbinger for diabetes, kidney and bone failure, and cancer. An area of intense interest where the role of adiposity is avidly discussed is in inflammatory bowel disease (IBD), which presents mainly as Crohn's disease (CD) and ulcerative colitis (UC). Studies in patients associating IBD with a western diet are divergent. Nevertheless, elegant studies have found gene polymorphisms in humans that in murine models parallel the inflammatory and gut microbiome changes seen in IBD patients. However, an area not to be ignored are the alterations in adipocyte function with ensuing adiposity, in particular and a focus of this review, the dysregulation of the levels of adipocytokines such as leptin and adiponectin. Herein, we present and discuss the known influences of a western diet on IBD in patients and rodent models and how adipocytokines could influence the IBD disease process.

Topics: Adipocytes; Adipokines; Adiponectin; Adiposity; Animals; Colitis, Ulcerative; Crohn Disease; Diet, Western; Disease Progression; Gastrointestinal Microbiome; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases; Leptin; Mice; Obesity; Polymorphism, Genetic; Risk Factors

The second scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal healing for the disease course of inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms, markers for disease prediction, detection and monitoring of intestinal healing, impact of intestinal healing on the disease course of IBD as well as therapeutic strategies. The results of this workshop are presented in four separate manuscripts. This section describes basic mechanisms of intestinal healing, identifies open questions in the field and provides a framework for future studies.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Butyric Acid; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Defensins; Extracellular Matrix; Humans; Immunosuppressive Agents; Infliximab; Intestinal Mucosa; Leptin; Matrix Metalloproteinases; Mesalamine; Paneth Cells; Probiotics; Reactive Nitrogen Species; Reactive Oxygen Species; Sulfasalazine; Tumor Necrosis Factor-alpha; Wound Healing

Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells, are involved in these manifestations of IBD. Among adipokines leptin, adiponectin and resistin hold a fundamental role while the role of ghrelin in inflammation is not well established. Preliminary studies have shown overexpression of leptin, adiponectin, and resistin in mesenteric WAT of patients with Crohn's disease (CD) and significant alterations of circulating serum levels of these adipokines in IBD. It has also been demonstrated that intestinal inflammation causes an increase in endogenous ghrelin production. In animal models of intestinal inflammation, existing data suggest that leptin, adiponectin, and resistin are pivotal mediators of inflammation. Interesting therapeutic interventions based on these data have been suggested. A specific role for hypertrophic WAT has also been implicated in CD. Further efforts with experimental and clinical studies are needed to better understand the role of adipokines in IBD.

Topics: Adiponectin; Adipose Tissue, White; Animals; Colitis, Ulcerative; Crohn Disease; Cytokines; Ghrelin; Humans; Hypertrophy; Inflammatory Bowel Diseases; Leptin; Resistin

Patients with Crohn's disease (CD) often develop malnutrition due to disease activity. We aimed to assess the effect of two different enteral supplements of Impact(R) Powder (IP; Novartis, Switzerland) on leptin levels and nutritional status in active CD patients during prednisolone treatment and tapering.. Thirty-one CD patients were randomized to IP Extra (group 1) or IP Standard (group 2). Leptin levels, nutritional, clinical and biochemical markers were studied at inclusion, after 5 and after 9 weeks of the study.. Leptin levels, body mass index (BMI) and total cholesterol increased significantly within both groups at week 5 compared to inclusion. Leptin levels correlated with BMI in both groups at inclusion and in group 2 at week 9. In group 1, triglyceride levels remained unchanged, while levels in group 2 increased significantly at week 5 compared to inclusion. Clinical and biochemical markers improved during the study compared to inclusion.. Increased leptin levels during the study progress were transient, decreasing due to prednisolone withdrawal at the end of the study. Both formulas used as adjuvant therapy to prednisolone treatment were able to improve nutritional status in CD patients.

Topics: Adolescent; Adult; Aged; Arginine; Body Mass Index; Crohn Disease; Dietary Supplements; Double-Blind Method; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Glucocorticoids; Humans; Leptin; Male; Middle Aged; Nutritional Status; Prednisolone; RNA

The expression of leptin and leptin receptor (Ob-R) has been partially elucidated in colon of patients with inflammatory bowel diseases (IBDs), even though leptin is involved in angiogenesis and inflammation. We previously reported overexpression of GLUT5 fructose transporter, in aberrant clusters of lymphatic vessels in lamina propria of IBD and controls. Here, we examine leptin and Ob-R expression in the same biopsies. Specimens were obtained from patients with ulcerative colitis (UC), Crohn's disease (CD) and controls who underwent screening for colorectal cancer, follow-up after polypectomy or with a history of lower gastrointestinal symptoms. Immunohistochemistry revealed leptin in apical and basolateral membranes of short epithelial portions, Ob-R on the apical pole of epithelial cells. Leptin and Ob-R were also identified in structures and cells scattered in the lamina propria. In UC, a significant correlation between leptin and Ob-R in the lamina propria was found in all inflamed samples, beyond non-inflamed samples of the proximal tract, while in CD, it was found in inflamed distal samples. Most of the leptin and Ob-R positive areas in the lamina propria were also GLUT5 immunoreactive in inflamed and non-inflamed mucosa. A significant correlation of leptin or Ob-R expression with GLUT5 was observed in the inflamed distal samples from UC. Our findings suggest that there are different sites of leptin and Ob-R expression in large intestine and those in lamina propria do not reflect the status of mucosal inflammation. The co-localization of leptin and/or Ob-R with GLUT5 may indicate concomitance effects in colorectal lamina propria areas.

Topics: Adult; Case-Control Studies; Colitis, Ulcerative; Colon; Crohn Disease; Female; Glucose Transporter Type 5; Humans; Intestinal Mucosa; Leptin; Male; Middle Aged; Receptors, Leptin; Young Adult

Adipose tissue secretes molecules that can promote activity in Crohn's disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn's disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn's disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34-22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.

Topics: Adipokines; Adiponectin; Adult; Biomarkers; Case-Control Studies; Crohn Disease; Female; Follow-Up Studies; Ghrelin; Humans; Leptin; Male; Middle Aged; Prognosis; Resistin; ROC Curve

Crohn's disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.

Topics: Adult; Biopsy; Caco-2 Cells; Case-Control Studies; Crohn Disease; Cyclic S-Oxides; Down-Regulation; Female; Humans; Intestinal Mucosa; Leptin; Male; MARVEL Domain Containing 2 Protein; Middle Aged; Pyridines; Receptors, Lipoprotein; STAT3 Transcription Factor; Transcription Factors; Tyrphostins; Young Adult

Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn's disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn's disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn's disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn's disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.

Topics: Cell Line; Crohn Disease; Humans; Inflammation; Killer Cells, Natural; Leptin; Lipodystrophy, Congenital Generalized; Male; Phenotype; T-Lymphocytes; Tumor Necrosis Factor-alpha; Wound Healing

The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD.. Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (μg/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 ± 1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 ± 1.6 years).. At baseline, CD patients (mean age 15.0 ± 1.5 years, 10 of 18 boys) compared with HC (13.4 ± 1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5); P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6; P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2; P = 0.0156) and 17.2 ng/mL (10.8- 26.8; P = 0.1953) at weeks 0, 2, and 14 respectively; with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6; P = 0.0840) and 3.3 (1.3-4.6; P = 0.1309). Adiponectin peaked initially from 7.8 μg/mL (4.6-11.9) at week 0 to 9.2 μg/mL (4.1-20.7; P = 0.0005) at week 2 and thereafter fell to 6.5 μg/mL (3.0-12.7; P = 0.0182) at week 14.. TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD.

Topics: Adiponectin; Adipose Tissue; Adolescent; Anti-Inflammatory Agents; Biomarkers; Case-Control Studies; Child; Crohn Disease; Female; Humans; Induction Chemotherapy; Infliximab; Leptin; Male; Resistin; Retrospective Studies

Determining inflammatory activity is crucial for assessing disease activity and for tailoring therapy in patients with Crohn׳s disease (CD). This study aimed to evaluate adipocytokine levels in patients with CD and to determine whether they can serve as surrogate markers for disease activity.. Serum samples and information regarding the clinical features of patients in the CD Network Project registry were collected from March 2009 to February 2012. Patients with CD and disease duration of at least 2 years were enrolled in this study. Fasting serum leptin, adiponectin, obestatin and ghrelin levels were measured, and their correlation with clinical features of the patients was analyzed. Serum adipocytokine levels were evaluated according to disease activity as determined by CD activity index score.. A total of 153 patients with CD were included. Serum ghrelin levels negatively correlated with patient age (P = 0.041) and age at diagnosis (P = 0.017), and positively correlated with C-reactive protein (CRP) levels (P = 0.017). Multiple regression analysis showed that serum ghrelin levels were related only to CRP levels (P = 0.032). Like ghrelin, serum leptin levels were also related to CRP levels (P < 0.001). Obestatin and adiponectin levels were not related to CRP levels. Serum adipocytokine levels did not significantly differ across different disease locations or behaviors. Serum ghrelin levels were significantly lower in patients with CD with a history of surgery than in those without (P = 0.007).. Serum ghrelin and leptin levels may be useful as surrogate markers for disease activity in patients with CD.

Topics: Adiponectin; Adult; Biomarkers; C-Reactive Protein; Crohn Disease; Fasting; Female; Ghrelin; Humans; Intestines; Leptin; Male; Middle Aged; Young Adult

Visceral adipose tissue (VAT) could affect Crohn's disease (CD); however, no prospective clinical studies have explored the issue.. We measured VAT with magnetic resonance imaging and total fat mass (FM) with air-displacement plethysmography in 31 women with CD in remission and 19 matched control women. We assessed the VAT/FM ratio as index of VAT accumulation, measured cytokines, and monitored clinical features (duration of remission, disease behavior, and outcome) in patients with CD retrospectively and prospectively. We also tested whether ultrasound could provide a surrogate marker of VAT in patients with CD.. Patients with CD had higher percentage of FM (37 ± 10% versus 31 ± 10%, P = 0.03), VAT (1885 ± 1403 mL versus 941 ± 988 mL, P = 0.02), and VAT/FM ratio (65 ± 24 mL/kg versus 37 ± 25 mL/kg, P = 0.004) than control women. In patients with CD, VAT/FM ratio was associated with leptin (P = 0.009) and interleukin 6 (P = 0.032) concentrations, and higher in short-term than in long-term remission (72.6 ± 27.1 mL/kg versus 54.8 ± 16.1 mL/kg, P = 0.079). Patients with CD with stricturing/fistulizing disease had a higher VAT/FM ratio than patients with nonstricturing/nonfistulizing behavior (79 ± 0.15 mL/kg versus 63 ± 28 mL/kg, P = 0.067). A higher baseline VAT/FM ratio was associated with an increased disease activity at follow-up (P = 0.029). The ultrasound-determined thickness between the abdominal wall and the aorta was strongly associated with VAT as measured by magnetic resonance imaging (P < 0.001).. VAT accumulation could be a prospective risk factor for increased disease activity in CD.

Topics: Adult; Body Composition; Case-Control Studies; Crohn Disease; Female; Humans; Interleukin-6; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Middle Aged; Prospective Studies; Retrospective Studies; Risk Factors; Ultrasonography; Young Adult

Mesenteric adipose tissue hypertrophy is a hallmark of Crohn's disease and can express various adipokines. Exclusive enteral nutrition could effectively induce remission in Crohn's disease with mechanisms largely unknown. We investigated whether exclusive enteral nutrition could modify mesenteric fat in patients with active Crohn's disease.. Sixteen patients who underwent resection for ileum Crohn's disease were studied. As a control group, eight patients without inflammatory bowel disease were enrolled. Before operation, eight Crohn's disease patients received exclusive enteral nutrition for four weeks, and the other patients had no nutritional therapy. The mesenteric fat samples were obtained during operation. Adipocyte size, adipokine production and topical C-reactive protein level were assessed.. The adipocyte size from patients treated with exclusive enteral nutrition was much larger than that from Crohn's disease patients without nutritional therapy. Furthermore, protein levels of proinflammatory adipokines such as TNF-alpha and leptin were lower while protein level of adiponectin was higher in these patients. As to mRNA level, the expression of adiponctin was up-regulated and leptin was down-regulated in the patients received enteral nutrition.. Exclusive enteral nutrition could ameliorate mesenteric fat alterations which are associated with intestinal injury in patients with Crohn's disease by restoring adipocyte morphology and diminishing the inflammatory environment of mesenteric fat.

Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Body Mass Index; C-Reactive Protein; Crohn Disease; Down-Regulation; Enteral Nutrition; Female; Humans; Interleukin-6; Leptin; Male; RNA, Messenger; Specimen Handling; Tumor Necrosis Factor-alpha; Up-Regulation; Young Adult

To investigate serum adipokine levels in inflammatory bowel disease (IBD) patients before treatment and after achieving clinical remission.. Serum concentrations of six adipokines (tissue growth factor-β1, adiponectin, leptin, chemerin, resistin, and visfatin) were studied in 40 subjects with active IBD [24 subjects with Crohn's disease (CD) and in 16 subjects with ulcerative colitis (UC)] before and after three months of therapy with corticosteroids and/or azathioprine. Clinical diagnoses were based on ileocolonoscopy, computed tomography or magnetic resonance enterography and histological examination of mucosal biopsies sampled during endoscopy. Serum levels of adipokines were assessed by an indirect enzyme-linked immunosorbent assay. The control group was comprised of 16 age- and sex-matched healthy volunteers.. Baseline leptin concentrations were significantly decreased in both types of IBD compared to controls (8.0 ± 9.1 in CD and 8.6 ± 6.3 in UC vs 16.5 ± 10.1 ng/mL in controls; P < 0.05), and significantly increased after treatment only in subjects with CD (14.9 ± 15.1 ng/mL; P < 0.05). Baseline serum resistin concentrations were significantly higher in CD (19.3 ± 12.5 ng/mL; P < 0.05) and UC subjects (23.2 ± 11.0 ng/mL; P < 0.05) than in healthy controls (10.7 ± 1.1 ng/mL). Treatment induced a decrease in the serum resistin concentration only in UC subjects (14.5 ± 4.0 ng/mL; P < 0.05). Baseline serum concentrations of visfatin were significantly higher in subjects with CD (23.2 ± 3.2 ng/mL; P < 0.05) and UC (18.8 ± 5.3 ng/mL; P < 0.05) than in healthy controls (14.1 ± 5.3 ng/mL). Treatment induced a decrease in the serum visfatin concentrations only in CD subjects (20.4 ± 4.8 ng/mL; P < 0.05). Serum levels of adiponectin, chemerin and tissue growth factor-β1 did not differ between CD and UC subjects compared to healthy controls and also were not altered by anti-inflammatory therapy. Clinical indices of IBD activity did not correlate with adipokine levels.. IBD modulates serum adipokine levels by increasing resistin and visfatin release and suppressing leptin production.

Topics: Adipokines; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Azathioprine; Biopsy; Case-Control Studies; Colitis, Ulcerative; Colonoscopy; Crohn Disease; Cytokines; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gastrointestinal Agents; Humans; Leptin; Magnetic Resonance Imaging; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Crohn's disease (CD) and ulcerative colitis (UC) result in metabolic consequences. We assessed circulating leptin and adiponectin concentrations and examined their relations to glucose metabolism in children with CD and UC.. Circulating morning fasting concentrations of leptin, adiponectin, glucose, and insulin were measured in 32 children with CD and 18 children with UC. Insulin resistance (IR) and β-cell function were evaluated by the updated homeostatic model assessments (HOMA2-IR and HOMA2-B).. Leptin was positively related to BMI z-scores overall and in the CD and the UC subgroups (P < 0.001). A negative correlation between leptin and disease activity was observed in the entire population (P = 0.034) and in the UC (P = 0.03) group. None of the assessed parameters was related to adiponectin. Fourteen percent of the participants were insulin resistant (15.6% in the CD group and 11.1% in the UC group), significantly more than expected (P < 0.001). Leptin was associated with HOMA2-IR (overall: r = 0.29, P = 0.045). Pathway analysis suggested that, overall, disease activity and BMI significantly affect leptin, which in turn is the only correlate of HOMA2-IR.. Disease activity was significantly and inversely related to leptin in children with inflammatory bowel disease (IBD). A significant proportion of the patients had increased IR, which is positively related to circulating leptin.

Topics: Adiponectin; Adolescent; Blood Glucose; Body Mass Index; Child; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Female; Glucose; Greece; Humans; Insulin; Leptin; Linear Models; Male; Statistics, Nonparametric

The creeping fat in Crohn's disease (CD) is infiltrated by macrophages; local adipokine levels are increased. This study aimed to link these observations to define a role for macrophages in the pathology of human CD.. Human peripheral blood CD14 cells were polarised in vitro into M1 and M2 macrophages. The effects on adipokine receptors, phenotypic surface markers, cytokines and chemokines were assessed after treatment with leptin and adiponectin. Immunohistochemistry visualised macrophage subtypes in samples of mesenteric fat tissue from patients with CD. The chemotactic potential of secreted macrophage products was determined by T cell migration and chemokine production in vitro.. Although both adipokines altered the phenotype and function of M1 and M2 macrophages, M2 macrophages were more susceptible. M1 responded to leptin by increased cytokine production, but the stronger effect was seen in M2 macrophages with high expression of interleukin (IL)-10, IL-6 and tumour necrosis factor α. Adiponectin exerted similar effects and led to upregulated mannose receptor expression by M2 macrophages. Large macrophage numbers within the mesenteric fat tissue of patients with CD comprise a unique infiltration predominantly of M2 macrophages, leading to an IL-10-rich environment. While leptin increased the potency of both subtypes to attract CD3 T cells, adiponectin only affected M2 macrophages.. The adipocyte-dependent microenvironment within the creeping fat of patients with CD modulates the local macrophage compartment to a preference for the M2 subtype. The findings in this study with human cells suggest a protective role for the mesenteric fat in CD in terms of an enveloping barrier with the potential to limit intestinal inflammation.

Topics: Adipocytes; Adiponectin; B7-1 Antigen; Biomarkers; Chemotaxis, Leukocyte; Crohn Disease; Cytokines; Humans; Immunohistochemistry; Lectins, C-Type; Leptin; Macrophages; Mannose Receptor; Mannose-Binding Lectins; Mesentery; Phagocytosis; Polymerase Chain Reaction; Receptors, Adiponectin; Receptors, Cell Surface; Receptors, Leptin; T-Lymphocytes

Appetite disturbance is an important nutritional issue in Crohn's disease (CD), but the biological basis is unclear. Satiety signals such as polypeptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are produced by enteroendocrine cells (EEC). In animal models, upregulation of EEC plays a mechanistic role in feeding disturbance and weight loss. We recently showed increased EEC activity in tissue from active small bowel CD. This study investigated EEC products in plasma in CD, and appetite-related symptoms.. Active CD patients and a healthy reference group were studied. Gut peptide responses to a mixed nutrient test meal were measured by ELISA. Symptoms were assessed by visual analogue score. A patient subset was re-studied in remission.. CD subjects displayed reduced appetite (p < 0.0001) before and after eating. Total PYY was increased 2.2-fold (p = 0.04) and correlated with nausea (p = 0.036) and bloating (p = 0.037) scores only in small bowel CD. Postprandial plasma ghrelin levels were also elevated. Leptin correlated with body mass index (p = 0.0001) and weight loss (p = 0.01). GLP-1 and GIP were not elevated. In remission, postprandial PYY and ghrelin reverted to control levels.. Enhanced EEC responses may directly and adversely affect appetite in CD patients through increased gut-brain signalling.

Topics: Adult; Aged; Appetite; Case-Control Studies; Crohn Disease; Enteroendocrine Cells; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Intestine, Small; Leptin; Male; Middle Aged; Peptide YY; Postprandial Period; Visual Analog Scale; Young Adult

Dendritic cells (DC) migrate to lymph nodes on expression of C-C motif chemokine receptor 7 (CCR7) and control immune activity. Leptin, an immunomodulatory adipokine, functions via leptin receptors, signaling via the long isoform of receptor, LepRb. Leptin promotes DC maturation and increases CCR7 expression on blood DC. Increased mesenteric fat and leptin occur early in Crohn's disease (CD), suggesting leptin-mediated change in intestinal CCR7 expression on DC as a pro-inflammatory mechanism. We have demonstrated CCR7 expression and capacity to migrate to its ligand macrophage inflammatory protein 3β in normal human ileal DC but not colonic or blood DC. In CD, functional CCR7 was expressed on DC from all sites. Only DC populations containing CCR7-expressing cells produced LepRb; in vitro exposure to leptin also increased expression of functional CCR7 in intestinal DC in a dose-dependent manner. In conclusion, leptin may regulate DC migration from gut, in homeostatic and inflammatory conditions, providing a link between mesenteric obesity and inflammation.

Topics: B7-1 Antigen; B7-2 Antigen; Case-Control Studies; CD40 Antigens; Cell Movement; Cellular Microenvironment; Colon; Crohn Disease; Dendritic Cells; Humans; Ileum; Leptin; Receptors, CCR7; Receptors, Leptin; STAT3 Transcription Factor

Crohn's disease (CD) is characterized by inflammation and an aetiology that is still unknown. Hypertrophy of mesenteric fat is a reflection of disease activity, as this fat covers the entire length of the affected area. Adipocytes synthesize leptin and adiponectin, adipocytokines responsible for pro- and anti-inflammatory effects. Therefore, we evaluated serum levels of adiponectin and leptin, as well as mesenteral expression of adiponectin in active CD and those in remission. Sixteen patients with ileocaecal CD followed at the Outpatient Clinic, Coloproctology Unit of University of Campinas Clinical Hospital, participated in the study. Analysis of serum adiponectin and leptin by enzyme-linked immunosorbent assay was performed in patients with active CD (ACD group), remission CD (RCD group) and in six healthy controls. Ten patients with active ileocaecal CD (FCD group) and eight patients with non-inflammatory disease selected for surgery were also studied. The specimens were snap-frozen and the expression of adiponectin was determined by immunoblot of protein extracts. Serum C-reactive protein levels were higher in the ACD group when compared to the others and no difference of body mass index was observed between the groups. Serum adiponectin was lower in the ACD group when compared to control, but no differences were seen when comparing the ACD and RCD groups. Mesenteric adiponectin expression was lower in the FCD group when compared to the FC group. Serum leptin was similar in all groups. The lower levels of serum and mesenteric adiponectin in active CD suggest a defective regulation of anti-inflammatory pathways in CD pathogenesis.

Topics: Adiponectin; Adipose Tissue; Adolescent; Adult; Antigens, CD; Body Mass Index; C-Reactive Protein; Crohn Disease; Female; Humans; Leptin; Male; Mesentery; Middle Aged; Young Adult

A high prevalence of bone loss is observed in patients with inflammatory bowel disease (IBD). Leptin, ghrelin, insulin-like growth factor (IGF)-1, and IGF binding protein (IGFBP)-3 have been suggested to interfere in the bone metabolism. The aim of this study was to investigate the role of these peptides in the development of osteoporosis in IBD.. One hundred and eighteen consecutive IBD patients were included. All patients underwent bone densitometry by dual energy x-ray absorptiometry at the femoral neck and lumbar spine levels. Serum samples were collected from all patients and analyzed for concentrations of the aforementioned peptides by radioimmunoassay.. Forty (33.9%) patients were normal, 55 (46.6%) were osteopenic, and 23 (19.5%) were osteoporotic. Positive statistically significant correlations were found between body mass index (BMI), leptin, IGFBP-3 levels, and the bone mineral density (BMD) of the femoral neck and lumbar spine. Moreover, an inverse statistically significant correlation was found between BMD of the femoral neck and the lumbar spine, and age, duration of the disease, and ghrelin levels. Multivariate analysis revealed that the most significant factors associated with the BMD were age and BMI. A weak but statistically significant correlation was found between IGFBP-3 and femoral neck BMD (P=0.045) and between ghrelin and spine BMD (P=0.039). No correlation was observed between leptin and BMD.. Low BMI is the most important independent risk factor for osteoporosis in IBD patients. There is no independent influence of leptin but ghrelin and IGFBP-3 may play a role in the bone metabolism in the IBD.

Topics: Absorptiometry, Photon; Adult; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Female; Femur Neck; Ghrelin; Humans; Inflammatory Bowel Diseases; Insulin-Like Growth Factor Binding Protein 3; Leptin; Lumbar Vertebrae; Male; Osteoporosis; Risk Factors

Adipokines are fat-derived hormones and cytokines with immune-modulating and metabolic properties. Most of them are associated with insulin resistance. The aim of the present investigation was to evaluate circulating levels of adipokines and glucose homeostasis in patients with inflammatory bowel disease (IBD) and to evaluate possible associations with the course and characteristics of the disease.. Serum leptin, resistin, visfatin, retinol-binding protein-4, adiponectin, glucose, insulin, and inflammatory parameters were analyzed in 93 patients with inactive IBD (49 with Crohn's disease [CD], 44 with ulcerative colitis [UC]), 35 patients with active IBD (18 with CD, 17 with UC), and 37 age- and body mass index-matched healthy controls. Ninety-two patients were followed for 6 mo.. Leptin was similar in patients with IBD and controls, whereas resistin and visfatin were increased in patients with active disease but not in those in remission. In active and inactive disease, adiponectin was decreased (P < 0.001) and retinol-binding protein-4 was increased (P < 0.001) compared with controls. About 60% of patients with IBD showed increased levels of insulin, whereas serum glucose remained normal, resulting in increased homeostasis model assessment values in most patients. Hyperinsulinemia was associated with the decrease in adiponectin (r = -0.572, P < 0.001) and proved to be an independent protective factor for 6-mo maintenance of remission (P = 0.016).. IBD led to largely similar alterations in circulating adipokines and hyperinsulinemia in patients with CD and those with UC. The unexpected protective effect of hyperinsulinemia on relapse rate denotes the role of the metabolic-inflammatory response as a modulator in IBD.

Topics: Adiponectin; Adolescent; Adult; Aged; Case-Control Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Hyperinsulinism; Inflammation Mediators; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Resistin; Retinol-Binding Proteins; Young Adult

There is evidence that adipocytokines play an important role in metabolism and in inflammation. Because human metabolism dramatically changes in inflammatory bowel disease (IBD) and chronic inflammation is the hallmark of the disease, we studied serum levels of leptin, adiponectin, resistin, and ghrelin in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with healthy controls (HC).. Leptin, adiponectin, resistin, and active ghrelin serum levels were measured in 100 IBD patients (46 UC and 54 CD) and in 60 matched HC using commercially available enzyme-linked immunosorbent assays. Leptin, adiponectin, resistin, and ghrelin levels were correlated with disease activity, type, localization, and treatment.. Mean serum leptin levels were 10.6+/-2.0 ng/mL in UC patients, 12.5+/-2.6 ng/mL in CD patients, and 15.0+/-1.8 ng/mL in HC (P=.01). Mean serum adiponectin levels were 9514.8+/-787.8 ng/mL in UC patients, 7651.1+/-613 ng/mL in CD patients, and 7270.6+/-559.4 ng/mL in HC (P=.05). Mean serum resistin levels were 21.2+/-2.2 ng/mL in UC patients, 18.7+/-1.6 ng/mL in CD patients and 11.8+/-0.6 ng/mL in HC (P=.0002). Mean serum ghrelin levels were 48.2+/-4.2 pg/mL in UC patients, 49.4+/-4.6 pg/mL in CD patients and 14.8+/-3.0 pg/mL in HC (P<.0001). Serum levels of these adipocytokines were not correlated with either C-reactive protein levels or the clinical indices of activity. No association between serum adipocytokines levels and disease localization in both UC and CD patients was found. Only serum ghrelin was significantly higher in ileal compared with colonic CD (P=.04).. Serum levels of adiponectin, resistin, and active ghrelin are increased whereas serum levels of leptin are decreased in patients with IBD. Further studies are needed to elucidate the role of adipocytokines in IBD.

Topics: Adiponectin; Adult; Analysis of Variance; Biomarkers; Case-Control Studies; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Disease Progression; Female; Ghrelin; Humans; Inflammatory Bowel Diseases; Leptin; Male; Middle Aged; Peptide Hormones; Predictive Value of Tests; Probability; Prognosis; Reference Values; Resistin; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

In mice, body weight is regulated by adipocyte-derived leptin. TNFalpha is a critical mediator of inflammation-induced cachexia in Crohn's disease (CD). The regulation of leptin by TNFalpha is poorly understood in CD. Pharmacological neutralization of TNFalpha with infliximab offers a unique opportunity to study TNFalpha-mediated regulation of leptin in CD patients.. We prospectively followed up CD patients treated with infliximab (n = 20). Body composition was assessed before and after treatment at 1 and 4 wk. Serum leptin, IL-6, soluble TNF receptor type II, and soluble intercellular antiadhesion molecule-1 levels were measured as well as cholesterol levels and free urinary cortisol. Because methylprednisolone (MP) increases leptin production in vivo, CD patients treated with MP (n = 9) were studied separately as a positive control group.. Infliximab induced clinical remission and a significant decrease in C-reactive protein (P < 0.01) and IL-6 (P < 0.05) levels in all CD patients and increased body weight (P = 0.013) at 4 wk. Leptinemia was significantly increased after infliximab administration at 1 wk (P = 0.014) and 4 wk (P < 0.001). This increase in serum leptin occurred early at 1 wk, when no significant weight and fat mass changes could be observed and was associated with the down-regulation of TNFalpha-regulated mediators, soluble TNF receptor type II (P = 0.015), and soluble intercellular antiadhesion molecule-1 (P = 0.007). Moreover, infliximab increased cholesterol levels at 1 wk (P = 0.001). Twenty-four-hour cortisol secretion was not altered by infliximab. Leptinemia increased at 1 wk after MP administration (P = 0.028).. Infliximab increases leptinemia in CD. This study suggests that TNFalpha exerts major inhibitory actions on leptin production in CD patients.

Topics: Adult; Antibodies, Monoclonal; Biomarkers; Body Mass Index; Crohn Disease; Female; Humans; Infliximab; Interleukin-6; Leptin; Male; Receptors, Leptin; Receptors, Tumor Necrosis Factor, Type II; Regression Analysis; Tumor Necrosis Factor-alpha; Weight Gain

To determine the concentrations of leptin and ghrelin, which have opposite effects on appetite, energy expenditure, and weight control, in the plasma of patients with Crohn's disease (CD), which is often associated with weight loss and malnutrition.. Plasma leptin and ghrelin 'concentrations were determined in 28 outpatients with CD by radioimmunoassay. Age- and sex-matched controls with and without Helicobacter pylori (H pylori) infection (28 for each) were enrolled in the study. Circulating levels of these hormones were assessed with respect to CD activity, disease localization and medical treatment.. There were no significant differences in ghrelin levels between CD patients and H pylori-negative controls. However, circulating ghrelin levels were significantly lower in H pylori-infected subjects than in CD patients and uninfected controls. Plasma leptin levels were comparable among the groups. Localization and medication profile had no significant impact on circulating ghrelin and leptin levels.. Apart from H pylori infection, CD itself has no significant influence on circulating ghrelin and leptin levels in the outpatients who were mostly in inactive state.

Topics: Adolescent; Adult; Case-Control Studies; Crohn Disease; Female; Ghrelin; Helicobacter Infections; Helicobacter pylori; Humans; Leptin; Male; Malnutrition; Middle Aged; Peptide Hormones; Weight Loss

Exclusive enteral feeding reduces inflammation and improves well being, nutrition and growth in children with active Crohn disease. Whether improved growth and increases in growth-related proteins are a consequence of improved nutrition or a reduced inflammation is not known. This study was undertaken to test the hypothesis that changes in growth-related proteins are related to decreased inflammation, rather than improvement in nutritional status.. Twelve children with active Crohn disease treated for 6-weeks with exclusive enteral feeding were studied at days 0, 3, 7, 14, 21, 28, and 56. The Paediatric Crohn's Disease Activity Index (PCDAI), weight, triceps skinfold thickness, and midupper arm circumference were recorded. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), insulin-like growth factor (IGF-I), IGF-binding protein (IGFBP-3), and leptin were measured at each visit. Wilcoxon matched-pairs signed-rank test was used to compare day 0 with follow-up data.. Significant improvements (P < 0.05) occurred by day 3 in inflammatory parameters (ESR, IL-6) and by day 7 in PCDAI, CRP, and IGF-I. These changes preceded any significant changes in nutritional parameters (weight-for-age Z score and midupper arm circumference day 14, triceps skinfold thickness day 21).. Early increases in IGF-I during treatment of Crohn disease are attributable to the anti-inflammatory effect of the enteral feed rather than nutritional restitution.

Topics: Adolescent; Anthropometry; Biomarkers; Blood Sedimentation; C-Reactive Protein; Child; Crohn Disease; Enteral Nutrition; Female; Humans; Inflammation; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Male; Nutritional Status; Statistics, Nonparametric; Time Factors; Treatment Outcome

Altered appetite and early satiety may promote anorexia associated with Crohn's disease. The aim of this study was to assess the impact of disease activity on subjective appetite parameters in Crohn's disease patients.. Seventeen patients with Crohn's disease and 15 healthy controls (8 M: 7 F, 34 (20-35) years) were studied. Subjects rated their hunger, desire to eat, fullness and level of satiety using visual analogue scales after an overnight fast. Subjects were reassessed after ingestion of 500 and 1000 ml water. Anthropometry was used to determine percentage body fat. Serum leptin & TNF- alpha levels were assessed using immunoassay. Disease activity was determined using the Harvey-Bradshaw index.. Hunger ratings for active Crohn's disease patients were significantly lower than controls at baseline (P<0.05). Desire to eat was lower in patients with active Crohn's disease than controls both at baseline (95% CI, 0.3 mm, 40.7 mm) and after ingestion of 500 ml water (95% CI, 1.25 mm, 51.9 mm) (P<0.05). Serum leptin concentrations were significantly associated with percent body fat (r=0.57;P<0.001) and, after correcting for body fat status, tended to be higher in patients with active Crohn's disease (mean 0.9 ng/ml/% body fat; SD 0.8 ng/ml/% body fat) compared with either patients with inactive disease (mean 0.4 ng/ml/% body fat; SD 0.3 ng/ml/% body fat) or healthy controls (mean 0.3 ng/ml/% body fat; SD 0.2 ng/ml/% body fat) (P=0.15, ns). Appetite parameters and serum leptin concentrations showed no significant correlation.. Subjective appetite parameters were altered in patients with active Crohn's disease. At baseline, patients with active Crohn's disease were less hungry than healthy controls and had less desire to eat. After ingestion of 500 ml of water, desire to eat was significantly less in patients with active disease as compared with healthy controls. Serum leptin concentration corrected for percent body fat tended to be higher in patients with active Crohn's disease compared with inactive Crohn's disease and healthy controls, but the differences did not reach statistical significance.

Topics: Adult; Anthropometry; Appetite; Body Composition; Case-Control Studies; Crohn Disease; Female; Humans; Hunger; Leptin; Male; Satiation; Tumor Necrosis Factor-alpha; Water

Pediatric inflammatory bowel disease is often associated with growth failure and inadequate energy intake. Although several circulating cytokines are known to be elevated in inflammatory bowel disease, the mechanism for the related anorexia has not been described. Leptin is a newly recognized circulating protein that is an important regulator of appetite and energy metabolism; leptin levels are elevated in several animal models of inflammation. This study was conducted to determine whether serum leptin levels are elevated in young patients with inflammatory bowel disease.. One hundred twelve children and young adults with Crohn's disease or ulcerative colitis were studied prospectively. Forty-two patients with other gastrointestinal illnesses were used as control subjects. Height, weight, erythrocyte sedimentation rate, serum albumin concentration, and clinical information were collected prospectively, and leptin was measured by radioimmunoassay of stored serum.. No significant differences in leptin levels were found among disease groups or control subjects. Body mass index and gender were the only independent predictors of serum leptin in all groups examined. Disease activity varied inversely with serum leptin in patients with Crohn's disease, but these differences were explained entirely by variations in body mass index.. The determinants of serum leptin were the same in young patients with inflammatory bowel disease as in normal populations, indicating that alterations in leptin levels are unlikely to mediate the anorexia and growth failure associated with this disease.

Topics: Adolescent; Adult; Body Mass Index; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Leptin; Male; Prospective Studies; Proteins