leptin and Inflammatory-Bowel-Diseases

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

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10-/- mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Gastrointestinal Tract; Humans; Immunity, Cellular; Inflammatory Bowel Diseases; Leptin; T-Lymphocytes, Regulatory

This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine.. Creeping fat can be distinguished from healthy adipose tissue by its distinctively small adipocytes, by a specific microenvironment defined by high levels of adipokines and by a dominant immune cell infiltration. In Crohn's disease transmural inflammation facilitates increased bacterial translocation into the creeping fat. Translocalizing antigens can directly activate (pre)adipocytes via innate receptors. Adipocyte-derived mediators modulate phenotype and function of innate and adaptive immune cells. Activated (pre)adipocytes and adipokine-modulated immune cells might support a degree of inflammatory activation within the creeping fat that allows competent immune defense against exogenous factors while preventing systemic inflammation.. Fat tissue as an active organ in health and disease has been ignored for too long. The last few years of research provided evidence for the complex metabolic and immunological functions of adipose tissue. On the basis of the available data, creeping fat in Crohn's disease exerts a protective function by a localized anti-inflammatory effect, thus preventing a systemic inflammatory response.

Topics: Adipokines; Adipose Tissue; Biomarkers; Humans; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Intestinal Mucosa; Leptin; Lipid Metabolism; Mesentery; Receptors, Adiponectin; Receptors, Cell Surface; Receptors, Leptin; Resistin

Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract.. Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail.. The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin.. Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity.

Topics: Animals; Gastric Emptying; Gastrointestinal Motility; Gastrointestinal Neoplasms; Gastrointestinal Tract; Humans; Inflammatory Bowel Diseases; Intestinal Absorption; Leptin

Topics: Adiponectin; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Leptin; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

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

Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.

Topics: Adipocytes; Adiponectin; Ghrelin; Humans; Inflammatory Bowel Diseases; Leptin; Mesentery; Peptide Hormones; Resistin

Reduced bone mass and the increased risk of fracture in gastrointestinal diseases have a multifactorial pathogenesis. Undoubtedly, genetics play an important role, but other factors such as systemic inflammation, malnutrition, hypogonadism, glucocorticoid therapy in inflammatory bowel disease (IBD) and other lifestyle factors, such as smoking or being sedentary, may contribute to reduced bone mass. At a molecular level the proinflammatory cytokines that contribute to the intestinal immune response in IBD and probably also in coeliac disease are also known to enhance bone resorption. The discovery of the role of the receptor to activated NFkappaB (RANK) interaction with its ligand RANKL in orchestrating the balance between bone resorption and formation may link mucosal and systemic inflammation with bone remodelling, since RANK-RANKL are also involved in lymphopoiesis and T-cell apoptosis. Low circulating leptin in response to weight loss in any gastrointestinal disease may be an important factor in reducing bone mass. This report will summarize current concepts regarding gastrointestinal diseases (primarily IBD, coeliac disease and postgastrectomy states) and low bone mass and fracture.

Topics: Bone and Bones; Bone Density; Celiac Disease; Diagnosis, Differential; Gastrectomy; Gastrointestinal Diseases; Humans; Inflammatory Bowel Diseases; Leptin; Nutritional Status; Osteomalacia; Osteoporosis; Risk Factors; Vitamin D

Topics: Cytokines; Hormones; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Leptin; Nutritional Status

Clinical and basic research continues to expand our understanding of the complex pathogenesis of inflammatory bowel diseases. The potential roles played by fatty acid intake, serum leptin, and nitric oxide in the promotion of intestinal inflammation in Crohn's disease and ulcerative colitis will be reviewed. In addition, important advances in the areas of bone disease, vitamin deficiency, growth failure, and home parenteral nutrition will be discussed.

Topics: Adult; Bone Diseases; Child; Humans; Inflammatory Bowel Diseases; Leptin; Nitric Oxide; Parenteral Nutrition, Home; Vitamin A; Vitamin E

Topics: Adipokines; Adult; Circadian Rhythm; Female; Humans; Inflammatory Bowel Diseases; Leptin; Male; Middle Aged; Poland; Prospective Studies; Resistin; ROC Curve; Severity of Illness Index; Sleep Wake Disorders; Surveys and Questionnaires; Young Adult

Inflammatory bowel disease (IBD) is associated with delay in gastric emptying, increase in ghrelin, and decrease in leptin. The aim was to investigate the correlation between gastroduodenal (GD) symptoms, gastric emptying, and serum levels of active ghrelin and leptin in IBD. Twenty-seven IBD patients and 26 healthy volunteers were asked to complete the Porto Alegre Dyspeptic Symptoms Questionnaire. A gastric emptying test for solids was performed using a C13 octanoic acid breath test. During this test, serum samples were collected for measuring active ghrelin and leptin concentrations by radioimmunoassay.. Patients with IBD demonstrated delayed gastric emptying compared with healthy volunteers. In patients with GD symptoms, the delay in gastric emptying was more pronounced, and there were significant correlations of satiety and vomiting with gastric emptying. Basal leptin, but not active ghrelin, increased in patients with GD symptoms compared with patients without these symptoms. There were negative correlations between basal active ghrelin with total Porto Alegre score and epigastric pain in IBD patients with GD symptoms. Key Messages: In IBD, satiety and vomiting were associated with delay in gastric emptying. Conversely, epigastric pain had a negative correlation with active ghrelin. Our results suggest that different pathophysiological mechanisms contribute to GD symptoms in IBD.

Topics: Adult; Aged; Breath Tests; Caprylates; Carbon Isotopes; Case-Control Studies; Duodenum; Female; Gastric Emptying; Ghrelin; Humans; Inflammatory Bowel Diseases; Leptin; Male; Middle Aged; Stomach

Adipose tissue secretes various proteins referred to as adipokines, being involved in inflammation. It was recognized that mesenteric adipose tissue (MAT) is altered by inflammation, and pathologies such as inflammatory bowel disease (IBD). The aim of this study was to investigate the alterations of the mesenteric adipose tissue in two experimental colitis models in mice adapted to obtain moderate colonic inflammation.. Colonic inflammation was obtained using two models, either DSS dissolved in drinking water or intra-colonic instillation of DNBS. The expression of adipokines (leptin and adiponectin) and inflammatory markers (IL-6, MCP-1, F4/80) was studied by qRT-PCR in the MAT of treated and control mice.. Observations of the colon and IL-6 plasma level determination demonstrated that DNBS treatment led to stronger inflammation. Colitis induced a decrease of mRNA encoding to leptin and adiponectin in MAT. In contrast, colonic inflammation led to an increase of mRNA encoding to IL-6, MCP-1 and F4/80, a specific marker of macrophages.. The mesenteric adipose tissue, in two models of moderate colitis, shows a loss of adipose profile and a strong increase of inflammatory pattern, close to the observations made in MAT of IBD patients. These data suggest that these pro-inflammatory modifications of MAT have to be taken into account in the pathophysiology of IBD.

Topics: Adiponectin; Adipose Tissue; Animals; Colitis; Dextran Sulfate; Dinitrofluorobenzene; Disease Models, Animal; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Leptin; Male; Mice; Mice, Inbred BALB C; Proteasome Endopeptidase Complex; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Obesity is a chronic inflammatory disease and a risk factor for disorders such as heart disease, diabetes, and cancer. A high-fat diet (HFD), a risk factor for obesity, has also been associated with inflammatory bowel disease (IBD). A proinflammatory state characterized by systemic and local increases in cytokine and chemokine levels are noted in both obesity and IBD, but it is unclear whether obesity is a risk factor for IBD. To examine any association between obesity and IBD, we chose FVB.129P2- Abcb1a(tm1Bor)N7 (Mdr1a(-/-)) mice, because this strain develops IBD spontaneously with age without a chemical or bacterial "trigger." In addition, its background strain, FVB, has been used for diet-induced obesity studies. Mdr1a(-/-) mice and wild-type (WT) mice were fed a HFD (∼60% calories from fat) or a low-fat diet (LFD; ∼11% calories from fat) for 12 wk. Obesity phenotypes examined included body weight measurements, glucose metabolism changes, and adiposity at termination of the study. IBD was determined by clinical signs, necropsy, and histopathology. We found that compared with those fed the LFD, both the Mdr1a(-/-) and WT mice fed the HFD had greater weight gains and elevated plasma leptin concentrations (P < 0.0001). When all mice were analyzed, weight gain was also associated with inflammation in mesenteric fat (R(2) = 0.5; P < 0.0001) and mesenteric lymph nodes (R(2) = 0.4; P < 0.0001). In contrast, the HFD was not associated with IBD in WT mice, whereas it exacerbated spontaneous IBD in Mdr1a(-/-) mice (P = 0.012; Fisher's exact test). Although a HFD and obesity were not associated with IBD in WT mice, our studies suggest that they are likely risk factors for IBD in a genetically susceptible host, such as Mdr1a(-/-) mice.

Topics: Adipose Tissue; Adiposity; Animals; Diet; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fatty Liver; Glucose Tolerance Test; Inflammatory Bowel Diseases; Insulin Resistance; Leptin; Male; Mice; Mice, Knockout; Obesity; Weight Gain

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

Children with inflammatory bowel disease (IBD) commonly have altered nutrition and growth. Measurement of serum leptin may enhance other modalities to assess the nutritional state of children with IBD. The aim of the present study was to define the nutritional status of children with newly diagnosed IBD by measuring anthropometry and serum leptin levels.. Twenty-eight children newly diagnosed with IBD and 56 age- and sex-matched controls were enrolled prospectively. Anthropometry (weight, height, and body mass index [BMI] expressed as z scores) and serum leptin levels were measured.. The children with IBD had lower mean BMI z scores and weight-for-age percentiles than controls (P = 0.05 and P = 0.01, respectively). The mean (standard deviation) serum leptin levels of the children with IBD were 2.4 (± 1.9) pg/mL, compared with 5.2 (± 4.6) pg/mL for controls (P = 0.01). The BMI percentile correlated positively with leptin levels in both groups. Following adjustment for BMI percentiles, serum leptin levels were lower in children with IBD than in controls (P = 0.02). Leptin levels did not correlate with serum markers of inflammation or disease activity scores.. Detailed and focused nutritional assessment should be an integral part of the management of all children with IBD. Children at the time of diagnosis of IBD have significant undernutrition and have lower serum leptin levels than controls. The inflammatory state in IBD appears not to alter leptin metabolism. Further study of the effect of leptin in IBD is required.

Topics: Adolescent; Anthropometry; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Humans; Infant; Inflammatory Bowel Diseases; Leptin; Male; Nutrition Assessment; Nutritional Status

Glucocorticoid therapy is widely used in clinical practice. However, treatment with steroids carries the risk of side effects. We investigated changes in serum adiponectin and leptin in response to systemic glucocorticoid treatment in 18 pediatric patients with inflammatory bowel disease and contrasted these findings to circulating glucocorticoid bioactivity measured with a mammalian cell bioassay. Interestingly, serum adiponectin levels at 2 to 4 weeks of therapy were significantly higher in patients who experienced acute glucocorticoid-related side effects (22.9 +/- 2.6 microg/mL, n = 7) than in those who did not (16.0 +/- 2.1 microg/mL, n = 11, P < 0.05). Serum leptin was not associated with side effects. Circulating adiponectin may serve as an early and readily available endogenous biomarker for acute glucocorticoid-related side effects in pediatric patients.

Topics: Adiponectin; Adolescent; Animals; Biomarkers; Child; Child, Preschool; Chlorocebus aethiops; COS Cells; Female; Glucocorticoids; Humans; Inflammatory Bowel Diseases; Leptin; Male; Pilot Projects

Tumour necrosis factor alpha is a critical mediator of inflammation-related altered metabolism in inflammatory bowel disease (IBD), possibly through its interaction with adipokines, which play an important role in IBD. Infliximab is a well established antitumour necrosis factor alpha treatment in IBD.. We studied serum levels of leptin, adiponectin and resistin in 20 IBD patients before and after infliximab treatment using commercially available enzyme-linked immunosorbent assays. The results were correlated with alterations of disease activity, BMI and C-reactive protein.. Infliximab induced clinical response or remission in 18 out of 20 treated IBD patients. Mean serum-leptin levels were 4.6+/-0.5 and 5.1+/-0.5 ng/ml (P=0.41), mean serum-adiponectin levels were 10513.9+/-1216.9 and 9653.5+/-1031.5 ng/ml (P=0.36) and mean serum-resistin levels were 26.3+/-4.1 and 13.9+/-1.4 ng/ml (P=0.004), before and after infliximab treatment, respectively. No significant correlation between the changes of BMI, C-reactive protein or the clinical indices of activity and alterations of the examined adipokines was found.. Serum levels of leptin and adiponectin had no significant alterations, whereas serum-resistin levels are significantly decreased after infliximab therapy in IBD patients, suggesting a possible proinflammatory status for resistin in IBD and a role as a marker of successful therapy.

Topics: Adiponectin; Adult; Antibodies, Monoclonal; Biomarkers; Body Mass Index; C-Reactive Protein; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Infliximab; Leptin; Male; Middle Aged; Peptide Hormones; Prospective Studies; Resistin; Tumor Necrosis Factor-alpha

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

Leptin, a peptide encoded by the obese (ob) gene, is primarily secreted by adipocytes and is a critical hormone that controls body weight due to its central effects. Recently, additional roles for leptin in the gastrointestinal tract have been suggested because gastric lining cells also produce and release leptin in response to meal-related stimuli. While gastric epithelia might thus directly contribute to circulating leptin following a meal, here we show that inflamed colonic epithelial cells express and release leptin apically into the intestinal lumen. In addition, we demonstrate leptin expression and secretion in vitro in epithelial cells. In response to luminal leptin, model intestinal epithelia critically activate the NF-kappaB, a key signaling system to pro-inflammatory stimuli. The inflammatory effect of luminal leptin was characterized in vivo in mice administered intrarectal leptin. Leptin induced epithelial wall damage and neutrophil infiltration that represent characteristic histological findings in acute intestinal inflammation. These observations provide evidence for an intraluminal biological signaling of leptin and a new pathophysiological role for intraluminal leptin during states of intestinal inflammation such as inflammatory bowel disease.

Topics: Animals; Colitis; Colon; Cytokines; Inflammatory Bowel Diseases; Intestinal Mucosa; Leptin; Mice; Models, Biological; NF-kappa B

A recent study reports that the interleukin-2 deficient (IL-2(-/-)) mouse model of autoimmune and inflammatory bowel disease (IBD) with elevated pro-inflammatory cytokine production has elevated leptin concentrations during food deprivation. The objective of this study was to examine whether increased tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, contributes to the abnormally elevated leptin in IL-2(-/-) mice.. Eight week old, IL-2(-/-) and wild-type control (IL-2(+/+)), male mice were fed regular laboratory mouse food for two weeks. At the end of the study, blood was collected in the fed state, IL-2(-/-) and IL-2(+/+) mice were injected with either anti-TNF-alpha monoclonal antibody or normal saline, and blood was collected in the starved state.. The IL-2(-/-) mice consumed less food and lost weight. Administration of anti-TNF-alpha antibody markedly reduced serum leptin concentrations in IL-2(-/-) and control mice after food deprivation. Serum leptin in the IL-2(-/-) mice not receiving anti-TNF-alpha antibody increased significantly in the starved state. Serum concentrations of TNF-alpha were higher in IL-2(-/-) mice compared to controls in both the fed and starved state.. These results suggest that elevated TNF-alpha may be one mechanism for the sustained elevated leptin observed in IL-2(-/-) mice during food deprivation.

Topics: Animals; Antibodies, Monoclonal; Apolipoproteins; Autoimmune Diseases; Disease Models, Animal; Food Deprivation; Inflammatory Bowel Diseases; Interleukin-2; Leptin; Male; Mice; Mice, Inbred C57BL; Random Allocation; Serum Amyloid A Protein; Tumor Necrosis Factor-alpha

Leptin, a protein with a cytokine-like structure, is produced predominantly by adipocytes. It appears to play a key role in immune responses by increasing the secretion of Th1 and pro-inflammatory cytokines. As fat-wrapping is a characteristic feature of Crohn's disease (CD), and as increased leptin levels have been reported in animal models of intestinal inflammation, this study investigated whether mesenteric adipose tissue could be a source of leptin in human inflammatory bowel disease (IBD).. To quantify the expression of leptin mRNA in mesenteric adipose tissue of patients with CD or ulcerative colitis (UC).. Specimens were obtained from mesenteric white adipose tissue close to healthy and inflammatory small intestine and/or colon in patients with CD or UC and, for controls, from apparently healthy mesentery of patients operated for carcinoma of the right colon. The expression of leptin mRNA was assessed by reverse transcription-competitive polymerase chain reaction.. Leptin mRNA levels were significantly higher in mesenteric adipose tissue of CD and UC patients than in controls (P<0.05). In CD and UC, concentrations were not significantly different in mesenteric fat specimens, whether contiguous to macroscopically normal or grossly abnormal intestine.. This study provides the first evidence of a novel abnormality of the mesentery of patients with IBD. Overexpression of leptin mRNA in mesenteric adipose tissue may contribute to (a) the inflammatory process, (b) enhancement of mesenteric TNF alpha expression in CD (as recently reported), and/or (c) the anorexia frequently reported during flares of IBD.

Topics: Adipose Tissue; Adult; Female; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases; Leptin; Male; Mesentery; RNA, Messenger

Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that chronic intestinal inflammation with increased proinflammatory cytokines elevates serum leptin concentration, thereby contributing to anorexia. This hypothesis was studied in interleukin-2-deficient (IL-2(-/-)) mice, a model of IBD with elevated proinflammatory cytokine production. IL-2(-/-), wild-type pair-fed and wild-type control male mice (8 wk old) were fed regular laboratory mouse food for 2 wk. The IL-2(-/-) and pair-fed groups consumed less food and lost weight. Serum leptin concentrations in the IL-2(-/-) mice in the fed state were lower than controls, but not different from pair-fed mice, and paradoxically increased in the starved state to levels significantly higher than both starved control and pair-fed groups. This result did not change when serum leptin was adjusted for amount of body fat. These data show abnormal leptin responses in IL-2(-/-) mice with increased leptin concentrations disproportionate to fat mass and prevention of the normal decline in leptin with food restriction.

Topics: Animals; Anorexia; Body Weight; Cytokines; Disease Models, Animal; Eating; Energy Intake; Food Deprivation; Inflammatory Bowel Diseases; Interleukin-2; Leptin; Male; Mice; Mice, Inbred C57BL; Wasting Syndrome

Leptin, a hormone primarily secreted from adipocytes, plays a key role in controlling body weight homeostasis. In vitro studies indicate that it is also implicated in immune responses. Hyperleptinaemia has been reported in acute inflammation, especially during the early stages of intestinal inflammation in rats. The present study investigated the possible role of leptin in the pathogenesis of trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Since no specific antagonist of leptin is available, a CCK-B antagonist (YM022) and a beta3 agonist (BRL37344) were used in this study to inhibit leptin secretion. Colitis was induced by intracolonic instillation of TNBS in rats. Five TNBS-groups were subcutaneously implanted with micropumps containing: placebo, YM022, BRL37344, BRL37344 and exogenous leptin simultaneously, or leptin alone. At sacrifices, colitis severity was assessed by macroscopic and histological scoring systems and by determination of tissue myeloperoxidase activity. The TNBS-induced hyperleptinaemia was significantly reduced by YM022 and BRL37344 (p<0.05). Inhibition of leptin secretion markedly reduced colonic inflammation, whatever the criteria considered (i.e. macroscopic, histological or biochemical). In contrast, administration of exogenous leptin completely abolished the beneficial effect of leptin-lowering drugs on colitis severity. These results provide the first direct evidence for an important deleterious role of leptin in the pathogenesis of experimental intestinal inflammation and suggest that a pro-inflammatory activity is attributable to leptin in vivo. Further studies are required to determine if these results have clinical significance.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Analysis of Variance; Animals; Benzodiazepines; Colitis; Disease Models, Animal; Ethanolamines; Hormone Antagonists; Inflammatory Bowel Diseases; Leptin; Male; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Receptors, Adrenergic, beta-3; Receptors, Cholecystokinin; Severity of Illness Index

Topics: Animals; Anorexia; Body Weight; Humans; Hypothalamus; Inflammatory Bowel Diseases; Leptin; Mice; Proteins

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

1. Leptin inhibits food intake and is an important regulator of long-term energy balance. In rodents, plasma concentrations of leptin are increased by administration of interleukin-1 and tumour necrosis factor. Hyperleptinaemia may mediate the anorexia and weight loss which is observed in chronic infections and inflammatory conditions. 2. Plasma leptin and soluble tumour necrosis factor receptor (sTNF-r55) concentrations were measured in patients with inflammatory bowel disease and acquired immunodeficiency syndrome (AIDS), and healthy controls. 3. The patients with AIDS were severely wasted [% body fat 12 (9-16); median (interquartile range)] compared with those with inflammatory bowel disease [25.1 (19-31.5)] and control subjects [29.4 (23.6-37.8)]. Leptin concentrations were highly correlated with percentage body fat in controls (r = 0.74, P < 0.001) and patients with IBD (r = 0.73, P < 0.001) but not in the patients with AIDS (r = -0.024). Leptin concentrations were similar in the inflammatory bowel disease [4.8 (2.6-10.1) ng/ml] and control groups [8.0 (3.1-14.1) ng/ml] but were significantly lower (P < 0.05) in patients with AIDS [1.8 (1.5-2.3) ng/ml] after 23 patients were matched for sex and percentage body fat in patients with inflammatory bowel disease [2.4 (1.8-4.1) ng/ml]. Plasma concentrations of sTNF-r55 were higher in both the patients with inflammatory bowel disease [0.19 (0.16-0.23) ng/ml] and those with AIDS [4.8 (2.8-7.3) ng/ml] compared with controls [0.14 (0.09-0.16) ng/ml] but were not correlated with either percentage body fat or plasma leptin concentrations. 4. Hyperleptinaemia does not appear to mediate the anorexia and weight loss associated with inflammatory bowel disease and AIDS. In patients with AIDS with extreme wasting there was no relationship between body fat and leptin and this may be related to the rapid weight loss which occurs in these patients.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anorexia; Body Composition; Female; Humans; Inflammatory Bowel Diseases; Leptin; Male; Proteins; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Statistics, Nonparametric; Weight Loss