leptin and Barrett-Esophagus

Central obesity is involved in the pathogenesis and progression of Barrett's esophagus to esophageal adenocarcinoma. Involved are likely both mechanical and nonmechanical effects. Mechanical effects of increased abdominal fat cause disruption of the gastroesophageal reflux barrier leading to increased reflux events. Nonmechanical effects may be mediated by inflammation, via classically activated macrophages, pro-inflammatory cytokines, and adipokines such as Leptin, all of which likely potentiate reflux-mediated inflammation. Insulin resistance, associated with central obesity, is also associated with both Barrett's pathogenesis and progression to adenocarcinoma. Molecular pathways activated in obesity, inflammation and insulin resistance overlap with those involved in Barrett's pathogenesis and progression.

Topics: Adiponectin; Barrett Esophagus; Gastroesophageal Reflux; Hernia, Hiatal; Humans; Inflammation; Insulin; Insulin Resistance; Leptin; Obesity, Abdominal

To investigate the feasibility and safety of a 24-week exercise intervention, compared to control, in males with Barrett's oesophagus, and to estimate the effect of the intervention, compared to control, on risk factors associated with oesophageal adenocarcinoma development.. A randomized controlled trial of an exercise intervention (60 minutes moderate-intensity aerobic and resistance exercise five days/week over 24 weeks; one supervised and four unsupervised sessions) versus attention control (45 minutes stretching five days/week over 24 weeks; one supervised and four unsupervised sessions) in inactive, overweight/obese (25.0-34.9 kg/m2) males with Barrett's oesophagus, aged 18-70 years. Primary outcomes were obesity-associated hormones relevant to oesophageal adenocarcinoma risk (circulating concentrations of leptin, adiponectin, interleukin-6, tumour necrosis factor-alpha, C-reactive protein, and insulin resistance [HOMA]). Secondary outcomes included waist circumference, body composition, fitness, strength and gastro-oesophageal reflux symptoms. Outcomes were measured at baseline and 24-weeks. Intervention effects were analysed using generalised linear models, adjusting for baseline value.. Recruitment was difficult in this population with a total of 33 participants recruited (target sample size: n = 80); 97% retention at 24-weeks. Adherence to the exercise protocol was moderate. No serious adverse events were reported. A statistically significant intervention effect (exercise minus control) was observed for waist circumference (-4.5 [95% CI -7.5, -1.4] cm; p < 0.01). Effects on primary outcomes were not statistically significant.. This small, exploratory trial provides important information to inform future trial development including recruitment rates and estimates of effect sizes on outcomes related to oesophageal adenocarcinoma risk. Future trials should investigate a combined dietary and exercise intervention to achieve greater weight loss in this population and relax inclusion criteria to maximize recruitment.. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000401257.

Topics: Adenocarcinoma; Adiponectin; Barrett Esophagus; C-Reactive Protein; Case-Control Studies; Esophageal Neoplasms; Exercise; Humans; Insulin Resistance; Interleukin-6; Leptin; Male; Middle Aged; Obesity; Overweight; Risk Factors; Tumor Necrosis Factor-alpha

Currently, the global prevalence of obesity among the worlds adult population is about 650 million people, which makes it possible to consider this chronic metabolic disease as a non-infectious pandemic of the 21st century. It has been proven that obesity is associated with several gastroenterological diseases, while the mechanisms of these associations are extremely heterogeneous and multifactorial. Hypertrophy and hyperplasia of adipocytes in obesity lead to a change in the profile of adipokine production (a decrease in adiponectin, an increase in leptin), an increase in the production of pro-inflammatory cytokines (interleukin-1, 6, 8, tumor necrosis factor ), C-reactive protein, free fatty acids, as well as active forms of oxygen (superoxide radicals, H2O2). All the above induces the development of chronic slowly progressive inflammation, oxidative stress, and insulin resistance. In addition, peptides secreted by adipocytes (adiponectin, leptin, nesfatin-1 and apelin) can modulate gastrointestinal motility, acting both centrally and peripherally. The qualitative and quantitative changes in the intestinal microbiota observed in obese patients (increased Firmicutes and decreased Bacteroidetes) lead to a decrease in the production of short-chain fatty acids and an increase in the intestinal permeability due to disruption of intercellular tight junctions, which leads to increased translocation of bacteria and endotoxins into the systemic circulation. Numerous studies have demonstrated the association of obesity with diseases of the esophagus (gastroesophageal reflux disease, Barretts esophagus, esophageal adenocarcinoma, esophageal motility disorders), stomach (functional dyspepsia, stomach cancer), gallbladder (cholelithiasis, gallbladder cancer), pancreas (acute pancreatitis, pancreatic cancer), liver (non-alcoholic fatty liver disease, hepatocellular carcinoma), intestine (diverticular disease, irritable bowel syndrome, colorectal cancer).. В настоящее время глобальная распространенность ожирения среди взрослого населения мира составляет около 650 млн человек, что позволяет рассматривать данное хроническое заболевание обмена веществ как неинфекционную пандемию XXI в. Доказано, что ожирение ассоциировано с целым рядом заболеваний гастроэнтерологического профиля, при этом механизмы этих связей крайне гетерогенны и мультифакториальны. Гипертрофия и гиперплазия адипоцитов при ожирении приводят к изменению профиля продукции адипокинов (снижение адипонектина, повышение лептина), повышению продукции провоспалительных цитокинов (интерлейкин-1, 6, 8, фактор некроза опухоли ), С-реактивного белка, свободных жирных кислот, а также активных форм кислорода (супероксидные радикалы, H2O2). Все перечисленное индуцирует развитие хронического медленно прогрессирующего воспаления, оксидативного стресса, а также инсулинорезистентности. Помимо этого, пептиды, секретируемые адипоцитами (адипонектин, лептин, несфатин-1 и апелин), способны модулировать моторику желудочно-кишечного тракта, действуя как центрально, так и периферически. Наблюдаемые у пациентов с ожирением качественные и количественные изменения микробиоты кишечника (повышение Firmicutes и снижение Bacteroidetes) приводят к сокращению продукции короткоцепочечных жирных кислот и росту проницаемости кишечной стенки вследствие нарушения межклеточных плотных контактов, что ведет к повышенной транслокации бактерий и эндотоксинов в системный кровоток. Многочисленными исследованиями продемонстрирована ассоциация ожирения с заболеваниями пищевода (гастроэзофагеальная рефлюксная болезнь, пищевод Баррета, аденокарцинома пищевода, нарушения моторики пищевода), желудка (функциональная диспепсия, рак желудка), желчного пузыря (желчнокаменная болезнь, рак желчного пузыря), поджелудочной железы (острый панкреатит, рак поджелудочной железы), печени (неалкогольная жировая болезнь печени, гепатоцеллюлярная карцинома), кишечника (дивертикулярная болезнь, синдром раздраженного кишечника, колоректальный рак).

Topics: Acute Disease; Adipokines; Adiponectin; Adult; Apelin; Barrett Esophagus; C-Reactive Protein; Cytokines; Digestive System; Endotoxins; Esophageal Neoplasms; Fatty Acids, Nonesterified; Humans; Hydrogen Peroxide; Interleukin-1; Leptin; Obesity; Oxygen; Pancreatitis; Risk Factors; Superoxides; Tumor Necrosis Factors

Abdominal obesity is a risk factor for Barrett's esophagus independent of GERD symptoms, but little is understood about the biological mechanisms between obesity and the carcinogenic pathway of esophageal adenocarcinoma.. To evaluate whether ghrelin and leptin may partially explain the association between obesity and Barrett's esophagus.. We conducted a case-control study using patients with a new diagnosis of Barrett's esophagus (cases) and two control groups frequency matched to cases for age, gender, and geographic region: (1) patients with gastroesophageal reflux disease (GERD) and (2) a sample of the general population. We generated odds ratios using logistic regressions to evaluate quartiles of serum ghrelin or serum leptin, adjusting for known risk factors for Barrett's esophagus. We evaluated potential interaction variables using cross products and ran stratified analyses to generate stratum-specific odds ratios.. A total of 886 participants were included in the analysis. Higher ghrelin concentrations were associated with an increased risk of Barrett's esophagus, when compared to the population controls, but not the GERD controls. Ghrelin concentrations were not associated with the frequency of GERD symptoms, but ghrelin's relationship with Barrett's esophagus varied significantly with the frequency of GERD symptoms. Leptin concentrations were positively associated with at least weekly GERD symptoms among the population controls and were inversely associated with Barrett's esophagus only among the GERD controls. Adjusting for waist circumference did not change the main associations.. Higher levels of ghrelin were associated with an increased risk of Barrett's esophagus among the general population. In contrast, leptin was positively associated with frequent GERD symptoms, but inversely associated with the risk of Barrett's esophagus among the GERD controls.

Topics: Adult; Aged; Barrett Esophagus; Biomarkers; California; Case-Control Studies; Female; Gastroesophageal Reflux; Ghrelin; Humans; Leptin; Logistic Models; Male; Middle Aged; Obesity, Abdominal; Odds Ratio; Risk Factors; Time Factors; Young Adult

Central adiposity is a risk factor for Barrett's esophagus (BE). Serum levels of adiponectin and leptin are deregulated in obese states and are implicated as putative mediators in the pathophysiology of esophageal columnar metaplasia. We describe associations between serum adiponectin and leptin levels with BE.. Patients were recruited prospectively for a case-control study. Fasting serum levels of adiponectin and leptin were measured in 135 patients with BE and compared with 2 separate control groups: 133 subjects with gastroesophageal reflux disease (GERD) and 1157 colon screening controls.. Multivariate analyses adjusted for age, race, and waist-to-hip ratio showed that patients within the highest tertile of serum adiponectin level had decreased odds of BE compared with screening colonoscopy controls (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.80). This effect was more pronounced in men (OR, 0.35; 95% CI, 0.17-0.74) compared with women (OR, 0.71; 95% CI, 0.17-3.03). In comparisons of BE cases with GERD controls, subjects within the highest tertile of serum adiponectin level showed decreased odds of BE (OR, 0.65; 95% CI, 0.31-1.36), however, this was not statistically significant. Patients in the highest tertile of serum leptin level did not have a significantly increased risk of BE in comparison with GERD (OR, 1.32; 95% CI, 0.61-2.88) or screening colonoscopy controls (OR, 1.57; 95% CI, 0.82-3.04) in analyses including both sexes. Based on sex-specific analyses, sex did not significantly alter the association of leptin with odds of BE.. Serum adiponectin was associated inversely with BE and this effect was more pronounced in men, whereas serum leptin showed no evidence of association with BE in comparisons with multiple control groups. The exact mechanism, if any, by which these adipokines promote metaplasia in the esophagus needs to be explored further.

Topics: Adiponectin; Adult; Aged; Barrett Esophagus; Case-Control Studies; Female; Humans; Leptin; Male; Middle Aged; Serum; Sex Factors

Topics: Adipokines; Adiponectin; Barrett Esophagus; Female; Gastroesophageal Reflux; Humans; Insulin; Leptin; Male; Serum

The pathogenesis of gastroesophageal reflux disease (GERD) is complex and poorly understood. We aim to investigate the association of various circulating peptide hormones with heterogenous manifestations of GERD.. One hundred and four patients that had experienced typical GERD symptoms (heartburn and/or acid regurgitation) for at least 3 episodes per week in the past 3 months were enrolled. All patients received a baseline assessment of symptom severity and frequency with the Reflux Disease Questionnaire and an upper endoscopy to classify GERD into erosive esophagitis (EE, n = 67), non-erosive esophagitis (NE, n = 37), and Barrett's esophagus (BE, n = 8). Fifty asymptomatic subjects with an endoscopically normal esophagus were recruited as the control group. Complete anthropometric measures and blood biochemistry were obtained and fasting serum levels of adipocytokines (adiponectin and leptin) and gut hormones (ghrelin and peptide YY (PYY)) were determined by enzyme-linked immunosorbent assay in all subjects.. All circulating peptide hormone levels were not statistically different between the GERD and control groups. However, GERD patients appeared to have lower PYY levels [median (25th-75th percentile), 80.1 (49.8-108.3) vs. 99.4 (65.8-131.9) pg/ml, p = 0.057] compared with control subjects. Among the GERD patients, ghrelin levels were inversely associated with the frequency and severity of acid regurgitation. In male GERD patients, EE was associated with significantly higher PYY levels [107.0 (55.0-120.8) vs. 32.8 (28.7-84.5) pg/ml, p = 0.026] but lower adiponectin levels [6.7 (5.6-9.3) vs. 9.9 (9.6-10.6) μg/ml, p = 0.034] than NE. Patients with BE had significantly lower adiponectin levels [6.0 (5.1-9.2) vs. 9.2 (7.1-11.2) μg/ml, p = 0.026] than those without BE.. Humoral derangement of circulating peptide hormones might participate in inflammation and symptom perception in patients suffering from GERD. Further studies to clarify the exact role of these hormones in the pathogenesis of GERD are warranted.

Topics: Adiponectin; Adult; Barrett Esophagus; Female; Gastroesophageal Reflux; Ghrelin; Heartburn; Humans; Leptin; Male; Middle Aged; Peptide YY; Surveys and Questionnaires

Obesity is associated with Barrett's esophagus (BE) and with changes in circulating levels of adipokines (leptin and adiponectin) and cytokines. Although studies have reported that adipokines and inflammatory cytokines are necessary for the development of BE, their role is controversial.. We performed a case-control study; cases (n = 141) were patients who underwent esophagogastroduodenoscopy and were found to have BE, which was based on endoscopy and histology, and controls (n = 139) were primary care patients eligible for screening colonoscopies who agreed to undergo esophagogastroduodenoscopy. We examined the association between BE and circulating levels of adipokines and cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, and IL-12p70; tumor necrosis factor-α; and interferon-γ). Cases and controls were compared by calculating odds ratios (ORs) and 95% confidence intervals (CIs) and using unadjusted and multiple logistic regression, adjusting for age, sex, race, waist-hip ratio, use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs, and Helicobacter pylori infection.. The adjusted ORs for BE were 2.62 (95% CI, 1.0-6.8), 5.18 (95% CI, 1.7-15.7), and 8.02 (95% CI, 2.79-23.07) for the highest quintile vs the lowest quintile of levels of IL-12p70, IL-8, and leptin, respectively, but the OR was not significant for IL-6 (2.39; 95% CI, 0.84-6.79). The adjusted OR for BE was 0.14 for highest quintile of IL-10 compared with lowest quintile (95% CI, 0.05-0.35) and 0.03 for IL-1β ≥ median vs none detected (95% CI, 0.006-0.13). Higher levels of IL-8 and leptin and lower levels of IL-10 and IL-1β were associated with the presence of long-segment (≥3 cm) and short-segment BE. There were no differences between cases and controls in levels of interferon-γ, tumor necrosis factor-α, adiponectin, or insulin.. BE is associated with circulating inflammatory cytokines and leptin and low levels of anti-inflammatory cytokines. These findings could partly explain the effect of obesity on BE.

Topics: Adipokines; Aged; Barrett Esophagus; Case-Control Studies; Cytokines; Female; Humans; Interleukins; Leptin; Male; Middle Aged; Obesity; Risk Assessment; Tumor Necrosis Factor-alpha

Risk prediction models for Barrett's esophagus (BE) have been developed using multiple demographic and clinical variables, but their predictive performance has been modest. Adding a multibiomarker risk score may improve discriminatory ability.. We used data from 141 patients with definitive BE and 138 controls participating in a case-control study at the Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX) (97% men, 65% of controls were white, and 89% of cases were white). We derived and compared 3 prediction models. Model 1 included only gastroesophageal reflux disease (GERD) frequency and duration; model 2 included GERD frequency and duration, age, sex, race, waist-to-hip ratio, and Helicobacter pylori status; and model 3 included the variables in model 2 as well as a multibiomarker risk score based on serum levels of interleukin (IL)12p70, IL6, IL8, IL10, and leptin. We assessed their predictive accuracy in terms of discrimination using the area under the receiver operating characteristic curve and calibration analyses.. The multibiomarker risk score was associated significantly with risk for BE. Compared with persons with a score of 0, persons with a score of 3 or higher had a greater than 10-fold increased risk for BE (biomarker risk score, ≥3; odds ratio, 11.9; 95% confidence interval, 4.06-34.9; P trend < .001). Risk prediction using the multibiomarker score in conjunction with demographic and clinical features improved discrimination compared with using only GERD frequency and duration (area under the receiver operating characteristic curve, 0.85 vs 0.74; P = .01).. Based on data from a case-control study of predominantly white male veterans, a risk prediction model including a multibiomarker score, derived from serum levels of cytokines and leptin, as well as GERD frequency and duration, age, sex, race, waist-to-hip ratio, and H pylori infection, can identify persons in this population with BE more accurately than previous methods.

Topics: Adult; Aged; Aged, 80 and over; Anthropometry; Barrett Esophagus; Biomarkers; Case-Control Studies; Cytokines; Demography; Female; Gastroesophageal Reflux; Humans; Leptin; Male; Middle Aged; Predictive Value of Tests; Risk Assessment

Individuals with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EA). Obesity contributes to the development of BE and its progression to cancer. We investigated the roles of obesity-induced hyperinsulinemia and dysregulation of adipokines in these processes.. We measured fasting levels of glucose, insulin, leptin, and adiponectin in 392 patients enrolled in the Seattle Barrett's Esophagus Study. We calculated homeostatic model assessment scores (a measure of insulin sensitivity) and identified subjects with metabolic syndrome. We evaluated the association between these measures and the risk of EA using Cox regression models adjusted for known risk factors.. Increasing homeostatic model assessment scores were associated with an increasing risk for EA; the strongest association was observed within the first 3 years after participants entered the study (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.43-4.1; P trend = .001). Leptin level also was associated significantly with an increased risk of EA within 3 years (HR, 2.51; 95% CI, 1.09-5.81; P trend = .03) and 6 years (HR, 2.07; 95% CI, 1.01-4.26; P trend = .048) of baseline. The level of high-molecular-weight adiponectin had a nonlinear inverse association with risk of EA; the strongest associations were observed in the second tertile (HR, 0.34; 95% CI, 0.14-0.82). Metabolic syndrome was not associated with risk of EA.. Among patients with BE, increased levels of leptin and insulin resistance are associated with increased risk for EA, whereas increased levels of high-molecular-weight adiponectin is associated inversely with EA. These biomarkers might be used to determine cancer risk among patients with BE.

Topics: Adenocarcinoma; Adiponectin; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers; Blood Glucose; Esophageal Neoplasms; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Risk Assessment

Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters.. Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p>0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11±0.08 vs. 0.19±0.24, p=0.78; 0.24±0.36 vs. 0.33±0.49, p=0.5375; 0.71±0.8 vs. 1.33±2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p<0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p<0.05).. in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity.

Topics: Adenocarcinoma; Adiponectin; Adult; Aged; Barrett Esophagus; Epithelium; Esophageal Neoplasms; Female; Humans; Leptin; Male; Middle Aged; Obesity, Abdominal; Receptors, Adiponectin; Receptors, Leptin

Insulin and leptin have proliferative and anti-apoptotic effects. Ghrelin promotes gastric emptying and secretion of growth hormone and inhibits inflammation. We assessed whether diabetes mellitus and serum levels of insulin, leptin, and ghrelin are associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus.. We conducted a case-control study in 822 men undergoing colorectal cancer screening who were recruited to also undergo upper endoscopy. We identified 70 with Barrett's esophagus; 80 additional men with Barrett's esophagus were recruited shortly after their clinical diagnoses. Serum levels of insulin, leptin, and ghrelin were assayed in all 104 fasting men with Barrett's esophagus without diabetes and 271 without diabetes or Barrett's esophagus. Logistic regression was used to estimate the effects of diabetes and levels of insulin, leptin, and ghrelin on GERD and Barrett's esophagus.. Among men with GERD, diabetes was inversely associated with Barrett's esophagus (adjusted odds ratio [OR] = 0.383; 95% confidence interval [CI]: 0.179-0.821). Among nondiabetics, hyperinsulinemia was positively associated with Barrett's esophagus, but the association was attenuated by adjustment for leptin and ghrelin. Leptin was positively associated with Barrett's esophagus, adjusting for obesity, GERD, and levels of insulin and ghrelin (OR for 3(rd) vs 1(st) tertile = 3.25; 95% CI: 1.29-8.17); this association was stronger in men with GERD (P = .01 for OR heterogeneity). Ghrelin was positively associated with Barrett's esophagus (OR for an increment of 400 pg/mL = 1.39; 95% CI: 1.09-1.76), but inversely associated with GERD (OR for 3(rd) vs 1(st) tertile = 0.364; 95% CI: 0.195-0.680).. Based on a case-control study, leptin was associated with Barrett's esophagus, particularly in men with GERD. Serum insulin level was associated with Barrett's esophagus, but might be mediated by leptin. Serum ghrelin was inversely associated with GERD, as hypothesized, but positively associated with Barrett's esophagus, contrary to our hypothesis. Additional studies are needed in men and women to replicate these findings.

Topics: Aged; Barrett Esophagus; Case-Control Studies; Diabetes Complications; Endoscopy, Gastrointestinal; Gastroesophageal Reflux; Ghrelin; Humans; Incidence; Insulin; Leptin; Logistic Models; Male; Middle Aged; Risk Factors

Persons diagnosed with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EA). Obesity is a major risk factor for both BE and EA. The primary purposes of this study were to determine whether circulating levels of leptin and adiponectin, both of which are deregulated in obese states, predict risk of specialized intestinal metaplasia (SIM) occurring in the esophagus (BE) and/or gastroesophageal junction, and evaluate the extent to which they mediate the relationship between obesity and these conditions. In this case-control study, 177 persons newly diagnosed with SIM were compared with 173 general population controls using unconditional logistic regression. Females in the highest tertiles of BMI and waist circumference were at the greatest risk (adjusted odds ratio (OR) = 4.6 (95% confidence interval (CI) = 1.9, 11.6), P(trend) = 0.002; OR = 5.1 (95% CI = 2.0, 13.0), P(trend) = 0.002, respectively) compared to females in the lowest tertiles. Adjustment for leptin and adiponectin attenuated these associations by 52 and 42%, respectively. Males in the highest tertile of waist-to-hip ratio were at the greatest risk (adjusted OR = 2.8 (95% CI = 1.3, 5.9), P(trend) = 0.014) compared to males in the lowest tertile. However, adjustment for leptin and adiponectin did not attenuate these associations. Our study results are consistent with the notion that circulating leptin and adiponectin partially mediate the obesity-BE relationship in women. Leptin and adiponectin's role in the progression from normal epithelium to SIM/BE and on to EA should be further elucidated.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Body Mass Index; Case-Control Studies; Esophagogastric Junction; Female; Humans; Leptin; Logistic Models; Male; Metaplasia; Middle Aged; Obesity; Odds Ratio; Risk Factors; Sex Factors; Waist-Hip Ratio; Young Adult

Obesity is a risk factor for esophageal adenocarcinoma, with a pathway through inflammation and metaplasia secondary to reflux the dominant hypothesis. The proinflammatory impact of adipocytokines associated with the metabolic syndrome of central adiposity may also be relevant. The objective of this study was to explore this profile in Barrett esophagus.. Patients with specialized intestinal metaplasia were invited to attend the metabolic syndrome screening where they underwent anthropometry, segmental bioelectrical impedance analysis, and blood pressure measurement, and had blood taken for quantification of fasting lipids, insulin, glucose, C-reactive protein, and adipocytokines.. One hundred two patients were studied. Forty-six percent of Barrett patients had metabolic syndrome and 78% were centrally obese. Patients with metabolic syndrome were significantly more obese by body mass index, had a 9.4 cm greater waistline, were more hypertensive, and were insulin resistant with 25% having fasting hyperinsulinemia compared with Barrett patients without metabolic syndrome. Metabolic syndrome was associated with elevated C-reactive protein, leptin, and a trend toward decreased adiponectin levels. Sixty percent of patients with long-segment Barrett had metabolic syndrome, and 92% were centrally obese compared with 23.8% and 62%, respectively (P = 0.007 and 0.005) in short-segment Barrett. Long-segment Barrett was associated with hyperinsulinemia and significantly increased levels of interleukin-6 compared with short-segment Barrett.. The prevalence of metabolic syndrome in Barrett far exceeds population norms, and the syndrome was significantly associated with the length of specialized intestinal metaplasia. The data do suggest that the metabolic syndrome may be relevant to the continuum of metaplasia within the Barrett cohort.

Topics: Adiponectin; Adiposity; Analysis of Variance; Anthropometry; Barrett Esophagus; Blood Glucose; Blood Pressure Determination; C-Reactive Protein; Chi-Square Distribution; Cytokines; Electric Impedance; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Phenotype; Prevalence; Resistin

Gastro-oesophageal reflux disease complications may reflect imbalances between protective and injurious factors. Through its effects on cell growth, leptin may influence oesophageal mucosal homeostasis.. To determine whether leptin receptors are present in the oesophagus, and whether serum or gastric leptin levels are associated with oesophageal inflammation and metaplasia.. From patients referred for upper endoscopy, biopsies were obtained from the stomach and distal oesophagus, and serum samples were collected. Patients were classified as having normal, inflamed or Barrett's oesophagus. Quantitative immunohistochemistry was performed on representative sections, and leptin levels in plasma and gastric biopsy samples were determined by specific immunoassay.. Of 269 individuals enrolled, 105 were Helicobacter pylori-negative. Of the 88 patients with complete oesophageal biopsies, 44 were normal, 24 were inflamed and 20 were Barrett's oesophagus. Receptors for leptin were highly expressed on oesophageal epithelial cells, with similar density and staining pattern in all three conditions, and plasma and antral leptin levels did not differ significantly. Patients with Barrett's had significantly (p = 0.01) higher fundic leptin levels (median 202 (interquartile range 123-333) pg/mg) compared with normal (126 (78-221) pg/mg) or inflamed (114 (76-195) pg/mg) oesophagus. In multivariate analysis, for every twofold increase in fundic leptin, the odds of having Barrett's was 3.4 times (95% CI 1.5 to 7.6) higher compared with having a normal oesophagus.. Leptin receptor expression on oesophageal epithelial cells provides a pathway for leptin-mediated signal transduction. Variation in gastric leptin production could contribute to differential oesophageal healing and metaplasia progression.

Topics: Barrett Esophagus; Endoscopy, Digestive System; Esophagitis; Esophagus; Female; Gastric Mucosa; Gastroesophageal Reflux; Humans; Leptin; Male; Metaplasia; Middle Aged; Receptors, Leptin; Retrospective Studies; Sensitivity and Specificity

Obesity is associated with increased risks of Barrett's oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis; however, the relationship with Barrett's oesophagus remains unexplored.. Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case-control study conducted in Brisbane, Australia. Cases were people aged 18-79 years with histologically confirmed Barrett's oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis.. In the pilot analysis (51 cases, 67 controls) risks of Barrett's oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett's oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett's oesophagus among women decreased with increasing serum leptin concentrations.. High serum leptin is associated with an increased risk of Barrett's oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.

Topics: Adiponectin; Adolescent; Adult; Age Distribution; Aged; Barrett Esophagus; Biomarkers; Body Mass Index; Female; Gastroesophageal Reflux; Humans; Leptin; Male; Middle Aged; Pilot Projects; Sex Distribution; Sex Factors

Obesity is an important risk factor for esophageal adenocarcinoma (EAC), and elevated serum leptin is characteristic of obesity. We hypothesized that leptin may have biological effects in promoting esophageal adenocarcinoma and examined the effects of leptin on the OE33 Barrett's-derived EAC line. Proliferation was assessed by dimethylthiazoldiphenyltetra-zoliumbromide and 5-bromo-2'-deoxyuridine incorporation assays and apoptosis by ELISA of intracellular nucleosomes. Intracellular signaling was examined using specific pharmacological inhibitors and direct detection of phosphorylated active kinases. Expression of the long and short leptin receptors by OE33 cells was confirmed by RT-PCR, Western blotting and immunocytochemistry. Leptin stimulated OE33 cell proliferation in a dose-dependent manner and inhibited apoptosis. These effects were dependent on cyclooxygenase (COX)-2 and replicated by adding prostaglandin E2 (PGE2). The effects of PGE2 and leptin were abolished by the EP-4 antagonist AH23848. ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and Janus tyrosine kinase (JAK)-2 were activated upstream of COX-2 induction, whereas the epidermal growth factor receptor and c-Jun NH2-terminal kinase (JNK) were downstream of COX-2. The activation of ERK and Akt but not p38 MAPK was JAK2 dependent. PGE2 stimulated phosphorylation of JNK in an EGF receptor-dependent manner, and activation of the epidermal growth factor receptor required protein kinase C, src, and matrix metalloproteinase activities. We conclude that leptin stimulates cell proliferation and inhibits apoptosis in OAC cells via ERK, p38 MAPK, phosphatidylinositol 3'-kinase/Akt, and JAK2-dependent activation of COX-2 and PGE2 production. Subsequent PGE2-mediated transactivation of the epidermal growth factor receptor and JNK activation are essential to the leptin effects. These effects may contribute to the greatly increased risk of esophageal adenocarcinoma in obesity.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Division; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Enzyme Activation; ErbB Receptors; Esophageal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Janus Kinase 2; JNK Mitogen-Activated Protein Kinases; Leptin; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Cell Surface; Receptors, Leptin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Recombinant Proteins; RNA, Messenger; Transcriptional Activation

Leptin is a hormone primarily produced by adipocytes and serum leptin is elevated in obese persons. One risk factor associated with adenocarcinoma of the esophagus is obesity. We hypothesized that leptin would have stimulatory effects on esophageal adenocarcinoma and alter apoptosis in vitro.. Barrett's esophageal adenocarcinoma cells (BIC-1 and SEG-1) were cultured with human recombinant leptin (80 ng/mL) for 24 hours. Cell growth was determined by MTT assay. Apoptosis and necrosis was measured after 16 hours of treatment with leptin using a Cell Death Kit.. Exogenous leptin stimulated cell proliferation in both cell lines. No changes in apoptosis or necrosis resulted between control and leptin-treated groups.. We have shown that leptin increases the proliferation of human esophageal adenocarcinoma, but does not alter cell apoptosis or necrosis. The data suggest that leptin stimulates esophageal adenocarcinoma growth by nonapoptotic mechanisms. Leptin antagonism may have potential efficacy in esophageal cancer therapy.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Cell Division; Enzyme-Linked Immunosorbent Assay; Esophageal Neoplasms; Humans; Leptin; Necrosis; Recombinant Proteins; Stimulation, Chemical; Tumor Cells, Cultured