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The Role of the Small Bowel in the Regulation of Circulating Ghrelin Levels and Food Intake in the Obese Zucker Rat

Institut de Recherche Contre les Canceurs de l’Appareil Digestif-European Institute of Telesurgery (F.R., A.F., M.V., J.M.), Université Louis Pasteur, 67091 Strasbourg, France; Institut National de la Santé et de la Recherche Médicale Unité 549 (P.Z., M.-T.B.-P., D.G.), 75014 Paris, France; Département de Pathologie Moléculaire (C.T.), Institut de Génétique et de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 6520 Centre National de la Recherche Scientifique/Unité 596 Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, 67404 Illkirch, France; and Istituto di Clinica Chirurgica (F.R.), Catholic University, 00168 Rome, Italy

Address all correspondence and requests for reprints to: Francesco Rubino, M.D., Institut de Recherche Contre les Canceurs de l’Appareil Digestif-European Institute of Telesurgery, 1 Place de l’Hopital, 67091 Strasbourg, France. E-mail: f.rubino{at}lycos.com.

Circulating levels of ghrelin, a stomach peptide that promotes food intake, rise before and fall after meal. We aimed to investigate whether there is an independent contribution of the small bowel to the regulation of ghrelin and appetite. A duodenal-jejunal bypass (DJB) with preservation of normal gastric volume and exposure to nutrients was performed in 12-wk-old obese Zucker ZDF fa/fa rat. Food intake, weight gain, 48-h fasting, and 24-h refeeding levels of total and acylated ghrelin were measured. The DJB was challenged against gastric banding (GB), diet, and a sham operation in matched animals. Normal controls were age-matched Wistar rats, which underwent either DJB or a sham operation. The Zucker obese animals showed a paradoxical increase of acylated ghrelin levels after refeeding (+30% with respect to fasting levels; P = 0.001), an abnormality that was completely reversed only by the DJB (–30%; P = 0.01) but not after GB, diet, or sham operation. In obese rats, the DJB resulted in significantly less food intake and weight gain compared with both GB (P < 0.05) and sham operation (P < 0.01). In sharp contrast, the DJB did not alter food intake and weight gain in normal rats. The DJB does not physically restrict the flow of food but restores meal-induced suppression of acylated ghrelin and significantly reduces food intake in Zucker obese rats. These findings suggest an independent intestinal contribution to the regulation of the dynamic ghrelin response to eating and the possibility that defective signaling from the proximal bowel could be involved in the pathogenesis of obesity/hyperphagia.

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