Mechanisms of action of leptin in preventing gastric ulcer

Abstract

Aim: To investigate the effects of leptin (1-20 microg/kg) on acidified ethanol (AE)- and indomethacin (Indo)-induced gastric lesions in rats and compare it with ranitidine, lanso-prazole, and omeprazole and to determine its mechanisms of actions.

Methods: Gastric ulcers, which were approximately 1 mm in width, formed in the glandular portion of the gastric mucosa produced by oral administration of either AE or Indo were taken as ulcer index. The inhibitory effect of subcutaneous administration of leptin, two proton pump inhibitors (PPIs) lansoprazole and omeprazole, or H(2)-receptor antagonist ranitidine 30 min before AE or Indo was evaluated. A radioimmunoassay was used to determine the PGE(2) concentration in the homogenate of the glandular portion of the stomach. We performed histological study of the glandular stomach for the evaluation of total, acidic, and sulfated mucus content.

Results: Subcutaneous administration of leptin, two PPIs lansoprazole and omeprazole or H(2)-receptor antagonist ranitidine 30 min before AE or Indo produced a dose-dependent and reproducible inhibition of gastric ulcers (GUs). This inhibition was found to be more potent than other antagonists used. In N(G)-nitro L-arginine methyl ester (L-NAME)-pretreated animals, the ulcer prevention ability of leptin in AE-induced ulcer was significantly reduced, compared to rats without L-NAME pretreatment. However, the ulcer prevention ability of leptin was not altered by L-NAME treatment in Indo-induced ulcers. Leptin produced a dose-dependent increase in PGE(2) level in the gastric glandular tissues. Leptin also increased mucus secretion.

Conclusion: The results of the present study show that leptin inhibits GU formation by AE or Indo in a dose-dependent and reproducible manner in rats. The results also suggest that leptin prevents ulcer formation by increasing the activities of the cyclo-oxygenase and/or nitric oxide pathways and by increasing mucus secretion.

Figure 1

Photomicrograph of macroscopic appearance of the glandular mucosa, showing the effect of AE (A) and Indo (C) in the absence (A and C) and presence of 10 μg/kg dose of leptin (B and D). These photographs are typical of six such tissues.

Figure 2

A: The ulcer indices of saline and different concentrations of leptin (1-50 μg/kg) against Indo. Each value is a mean±SE. Asterisks indicate significant difference when compared to saline control (^aP < 0.05, ^bP < 0.01); B: The degree of prevention of Indo-induced ulcerations after treatment with different doses of lansoprazole and omeprazole (each used at 1-10 mg/kg), leptin (10 μg/kg) and ranitidine (50 mg/kg). Each value is a mean±SE. Asterisks indicate significant difference (^dP < 0.001) when compared to saline control.

Figure 3

The effect of increasing doses of leptin (1-10 μg/kg), lansoprazole (1-10 mg/kg), and omeprazole (0.5-10 mg/kg) on AE-induced ulceration in rats. Each value is a mean±SE. Asterisks indicate significant difference, ^aP < 0.05, ^bP < 0.001 vs controls.

Figure 4

The ulcer prevention ability of leptin (10 μg/kg), when Indo was used to induce ulcer in L-NAME-pretreated animals. Each value is a mean±SE. Asterisks indicate significant difference, ^bP < 0.001 vs controls.

Figure 5

The ulcer prevention ability of leptin (10 μg/kg), in AE-induced ulcer after Indo or L-NAME pretreatment. Each value is a mean±SE. Asterisks indicate significant difference, ^bP < 0.001 vs controls. ^dP < 0.001 shows the significant difference in the effect of leptin on saline-treated and L-NAME-pretreated rats.

Figure 6

The effect of increasing doses of leptin (1-10 μg/kg) on AE-induced ulcer and prostaglandin E₂ levels in the gastric glandular mucosa in rats. Each value is a mean±SE. ^bP < 0.01, ^dP < 0.001 indicate significant difference in percentage ulcer index compared to AE-treated rats taken as 100%. ^fP < 0.01 shows the significant difference in the level of prostaglandin E₂ compared to AE-treated rats taken as 100%.

Figure 7

Gastric mucosal layer of rats stained with PAS showing (A) normal epithelium from control rats; (B) damaged epithelium (●) and (C) repaired epithelium after leptin treatment. Lower panel shows the AB (pH 1.0) staining showing mucus in (D) normal epithelium; (E) loss of epithelial mucus due to AE (★) and (F) presence of epithelial mucus after leptin treatment (bar = 6 μm; magnification 40×).