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Peripheral Interaction of Ghrelin with Cholecystokinin on Feeding Regulation

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; Daiichi Suntory Biomedical Research Co., Ltd. (S.K.), Osaka 681-8513; National Cardiovascular Center Research Institute (M.M., K.K.), Osaka 565-8565; and Department of Physiology (A.N.), Niigata University School of Medicine, Niigata 951-8510, Japan

Address all correspondence and requests for reprints to: Yukari Date, M.D., Ph.D., Third Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan. 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, whereas 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 their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats. Intravenous administration of ghrelin increased 2-h food intake in both OLETF and LETO rats. Because OLETF rats are CCK insensitive, iv-administered CCK decreased 2-h food intake in LETO, but not in OLETF, rats. Although preadministration of CCK to LETO rats blocked food intake induced by ghrelin, CCK preadministration to OLETF rats did not affect ghrelin-induced food intake. Conversely, preadministration 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, they 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 preadministration. Using immunohistochemistry, we also demonstrated the colocalization of GH secretagogue receptor (GHS-R), the cellular receptor for ghrelin, with CCK-AR in vagal afferent neurons. 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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