leptin and Metaplasia

Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33.. In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay.. Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro.. Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.

Topics: Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Goblet Cells; Inflammation; Interleukin-33; Leptin; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity

Excess of fat intake leads to obesity and causes a variety of metabolic diseases and cancer. We previously demonstrated that high-lard diet induces intestinal metaplasia, a precancerous lesion of the stomach mediated by leptin signaling. This study aims to investigate which kinds of dietary fat cause the intestinal metaplasia onset. We fed eight kinds of high-fat diets (HFDs) of animal or plant origin to mice evaluated their effect on gastric pathogenesis. Five types of dietary fat were divided according to their observed effects: Obese with high metaplasia (group I; beef tallow, lard, and hydrogenated coconut oil), non-obese with high metaplasia (group II; linseed oil), obese without metaplasia (group III; corn oil and olive oil), non-obese without metaplasia (group IV, soybean oil) and lean without metaplasia (group V; cocoa butter). The group I and II diets induced leptin, phosphorylated leptin receptor (ObR), signal transducer and activator 3 (STAT3), and increased intracellular β-catenin accumulation in the stomach. Moreover, mice fed these HFDs with 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), a gastric carcinogen, and further accelerated dysplasia in the stomach.

Topics: Animals; beta Catenin; Carcinogenesis; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Gastric Mucosa; Leptin; Metaplasia; Mice; Obesity; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Stomach

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake. Overexpression of TFF3 using a recombinant adeno-associated virus (AAV) vector, or daily administration of recombinant TFF3 protein in vivo improved glucose tolerance in a diet-induced obesity mouse model. Body weight, fasting insulin, triglyceride, cholesterol and leptin levels were not affected by TFF3 treatment. Induction of mucinous metaplasia was observed in mice with AAV-mediated TFF3 overexpression, however, no such adverse histological effect was seen after the administration of recombinant TFF3 protein. Altogether these results suggest that the therapeutic potential of targeting TFF3 to treat T2D may be limited.

Topics: Animals; Blood Glucose; Cholesterol; Dependovirus; Diet, High-Fat; Duodenum; Eating; Gene Expression; Gene Expression Regulation; Genetic Vectors; Glucose Tolerance Test; Humans; Ileum; Insulin; Jejunum; Leptin; Male; Metaplasia; Mice; Mucins; Obesity; Recombinant Proteins; Signal Transduction; Trefoil Factor-2; Trefoil Factor-3; Triglycerides

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

Serological screening for gastric cancer (GC) may reduce mortality. However, optimal serum markers for advanced gastric precursor lesions are lacking.. To evaluate in a case-control study whether serum leptin levels correlate with intestinal metaplasia (IM) and can serve as a tool to identify patients at high risk for GC.. Cases were patients with a previous diagnosis of IM or dysplasia, controls were patients without such a diagnosis. All patients underwent endoscopy. Fasting serum was collected for the measurement of leptin, pepsinogens I/II, gastrin, and Helicobacter pylori. Receiver operating characteristic (ROC) curves and their area under the curve (AUC) were provided to compare serum leptin levels with other serological markers.. One hundred nineteen cases and 98 controls were included. In cases, the median leptin levels were 116.6 pg/mL versus 81.9 pg/mL in controls (p = .01). After adjustment for age, sex and BMI, leptin levels remained higher in cases than in controls (p < .005). In multivariate analysis, male sex (p = .002), age (<0.001), low pepsinogen levels (p = .004) and high leptin levels (p = .04) were independent markers for the presence of IM. In addition, a ROC curve including age, sex and pepsinogen I levels had an AUC of 0.79 (95% CI (0.73-0.85)). Adding serum leptin levels increased the AUC to 0.81 (95% CI (0.75-0.86)).. High leptin levels are associated with an increased risk of IM. Moreover, serum leptin levels are a significant independent marker for the presence of IM. However, in combination with the serological test for pepsinogen I the additional value of serum leptin levels is rather limited.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Female; Helicobacter Infections; Helicobacter pylori; Humans; Intestines; Leptin; Male; Metaplasia; Middle Aged; Risk Factors; Stomach Neoplasms; Young Adult

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