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Background & Aims: Recent studies suggest that leptin, a hormone involved in food intake regulation, released into the circulation and gastrointestinal juice, may be a growth factor for intestine and may be involved in carcinogenesis; however, data are contradictory. This study investigates in rat colonic mucosa (1) the effects of hyperleptinemia on epithelial cell proliferation and development of aberrant crypts, earliest preneoplastic lesions, and (2) whether luminal leptin affects cell proliferation. Methods: Leptin (1 mg/kg/d) or vehicle was administered systemically by miniosmotic pump in Fischer 344 rats either for 7 days (BrdU-labeling indices study) or 23 days (azoxymethane-induced colonic lesions study). The effects of injections or continuous infusion of leptin into the colon were also studied. Results: In systemic leptin-treated rats, plasma leptin levels were 4- to 5-fold increased (P < 0.008 to P < 0.001); labeling indices were higher in proximal colon than in pair-fed control rats (P = 0.006) but unaffected in distal colon. Unexpectedly, in azoxymethane-treated rats, leptin significantly inhibited aberrant crypt foci formation in the middle and distal colon compared with controls (P = 0.006). Under these conditions, plasma insulin levels were reduced by 41%-58%, but gastrin levels were unchanged. In controls, luminal immunoreactive leptin reached the colon. A 3.6-fold increase in intraluminal leptin had no effect on epithelial cell proliferation. Conclusions: This study provides the first evidence that leptin reduces the development of chemically induced precancerous lesions in colon, perhaps through decreased insulinemia, and thus does not support an important role for leptin in carcinogenesis promotion. Moreover, the study indicates that leptin is not a potent growth factor for normal intestine.

Background & Aims:Leptin production has been reported in the rat and in human stomach. It initiates intestinal nutrient absorption. In this study, we analyzed the effect of vagal stimulation on leptin release in the human stomach. Methods:We studied the secretion of gastric acid and leptin on stimulation with insulin (a stimulant of vagal pathways via hypoglycemia) and pentagastrin in 11 healthy men (normal endoscopy and normal histological gastric mucosa), 5 with previous highly selective vagotomy (HSV), and 6 without HSV. Fundic biopsies were performed for immunostaining of leptin. Results:There was no difference between the 2 groups with respect to age, body mass index, basal leptin (4.8 +/- 1.2 ng/15 minutes) and gastric acid (0.7 +/- 0.2 mmol/15 minutes) outputs. Leptin-immunoreactivity was found in the fundic glands, and its distribution and density were similar in 2 groups. Insulin caused a rapid (15-minute) increase in leptin output in men without HSV (31 +/- 9 ng/15 minutes), but not in those with HSV (7.7 +/- 3.2 ng/15 minutes). Insulin-stimulated gastric leptin was biphasic, with a rapid increase (15 minutes after injection) followed by a second steady and sustained increase (39.9 +/- 7.6 ng/15 minutes at 120 minutes after injection). Pentagastrin increased gastric leptin output in individuals with (30 +/- 4.9 ng/15 minutes) and without (26 +/- 3.2 ng/15 minutes) HSV. Insulin and pentagastrin did not modify plasma leptin, whatever HSV status. Conclusions:Vagal stimulation of leptin release in the human stomach suggests that leptin is released during the cephalic phase of gastric secretion. Luminal leptin may be involved in vagus-mediated intestinal functions.

Background & Aims:: Leptin is a circulating hormone that communicates the peripheral nutritional status to the hypothalamus, which controls food intake, energy expenditure, and body weight. This study characterizes leptin receptors and leptin-sensitive STAT proteins in the antrum and investigates the effects of leptin on gastric secretions. Methods:: The effects of leptin on gastrin messenger RNA (mRNA), plasma gastrin, gastric acid in vivo in the rat, and on somatostatin and gastrin secretions by isolated antral cells were determined in vitro. Leptin receptors were investigated in isolated rat antral cells by reverse transcription-polymerase chain reaction and binding of [^1^2^5I]-leptin studies. The effects of in vivo and in vitro leptin on transduction signal STAT proteins were investigated by immunoblotting antral extracts. Results:: Peripheral injection of leptin inhibited in a dose-dependent manner, basal gastric secretion, gastrinemia, and mucosal gastrin mRNA in vivo. mRNAs encoding the long (Ob-Rb) and short (Ob-Ra) receptor forms were detected in rat antral mucosa, as were STAT-1, -3, and -5b immunoreactive proteins. Isolated antral cells specifically bound [^1^2^5I]-leptin, and addition of leptin to these cells inhibited the release of somatostatin and increased the release of gastrin. These effects were associated with an increase in nuclear STAT-3 proteins in vitro and in vivo. Conclusions:: This study provides the first molecular evidence for the coexpression of leptin receptors and STAT-3 in antral mucosa. It provides further evidence for the involvement of leptin in the control of gastric secretions.