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Submitted on September 17, 2004
Accepted on April 25, 2005
Third Department of Internal Medicine (Y.D., K.T., S.K., T.S., T.T., M.N.), Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan; Daiichi Suntory Biomedical Research Co., Ltd. (S.K.), Osaka 681-8513, Japan; National Cardiovascular Center Research Institute (M.M, K.K.), Osaka 565-8565, Japan; Department of Physiology (A.N.), Niigata University School of Medicine, Niigata 951-8510, Japan
* To whom correspondence should be addressed. E-mail: dateyuka{at}med.miyazaki-u.ac.jp.
Ghrelin and Cholecystokinin (CCK) are gastrointestinal hormones regulating feeding. Both transmitted via the vagal afferent, ghrelin elicits starvation signals, while CCK induces satiety signals. We investigated the interaction between ghrelin and CCK functioning in short-term regulation of feeding in Otsuka Long-Evans Tokushima fatty (OLETF) rats, which have a disrupted CCK type A receptor (CCK-AR), and lean littermates, Long-Evans Tokushima Otsuka (LETO) rats. Intravenous (iv) administration of ghrelin increased 2-h food intake in both OLETF and LETO rats. As OLETF rats are CCK-insensitive, iv-administered CCK decreased 2-h food intake in LETO, but not in OLETF, rats. While pre-administration of CCK to LETO rats blocked food intake induced by ghrelin, CCK pre-administration to OLETF rats did not affect ghrelin-induced food intake. Conversely, pre-administration of ghrelin to LETO rats blocked feeding reductions induced by CCK. In electrophysiological studies, once gastric vagal afferent discharges were altered by ghrelin or CCK administration, it could not be additionally affected by serial administrations of either CCK or ghrelin, respectively. The induction of Fos expression in the hypothalamic arcuate nucleus by ghrelin was also attenuated by CCK pre-administration. We also demonstrated the colocalization of growth-hormone secretagogue receptor (GHS-R), the cellular receptor for ghrelin, with CCK-AR in vagal afferent neurons by immunohistochemistry. These results indicate that the vagus nerve plays a crucial role in determining peripheral energy balance. The efficiency of ghrelin and CCK signal transduction may depend on the balance of their respective plasma concentration and/or on interactions between GHS-R and CCK-AR.
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