CCK inhibits the orexigenic effect of peripheral ghrelin

1 Department of Medicine, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum and 4 Department of Medicine, Division of Psychosomatic Medicine and Psychotherapy, and 5 Institute of Anatomy, Section of Electron Microscopy and Neuroanatomy, Campus Charité Mitte, Charité, Freie Universität and Humboldt-Universität Berlin, Berlin; 3 Robert-Koch-Institute, Berlin; 2 Department of Medicine, Division of Gastroenterology and Endocrinology, Philipps-Universität Marburg, Marburg, Germany; and 6 Department of Medicine, CURE Digestive Diseases Research Center, Center for Neurosvisceral Sciences, Digestive Diseases Division UCLA, and Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California Submitted 11 February 2004 ; accepted in final form 26 October 2004 CCK and ghrelin exert antagonistic effects on ingestive behavior. The aim of the present study was to investigate the interaction between ghrelin and CCK administered peripherally on food intake and neuronal activity in specific hypothalamic and brain stem nuclei, as assessed by c-Fos-like immunoreactivity (c-FLI) in nonfasted rats. Ghrelin (13 µg/kg body wt) injected intraperitoneally significantly increased the cumulative food intake when measured at 30 min and 1 h after injection, compared with the vehicle group (2.9 ± 1.0 g/kg body wt vs. 1.2 ± 0.5 g/kg body wt, P < 0.028). Sulfated CCK octapeptide (CCK-8S) (2 or 25 µg/kg body wt) injected simultaneously blocked the orexigenic effect of ghrelin (0.22 ± 0.13 g/kg body wt, P < 0.001 and 0.33 ± 0.23 g/kg body wt, P < 0.0008), while injected alone, both doses of CCK-8S exerted a nonsignificant trend to reduce food intake. Ghrelin (13 µg/kg body wt ip) markedly increased the number of c-FLI-positive neurons per section in the arcuate nucleus (ARC) compared with vehicle (median: 31.35 vs. 9.86, P < 0.0001). CCK-8S (2 or 25 µg/kg body wt ip) had no effect on neuronal activity in the ARC, as assessed by c-FLI (median: 5.33 and 11.21 cells per section), but blocked the ghrelin-induced increase of c- fos expression in this area when both peptides were administered simultaneously (median: 13.33 and 12.86 cells per section, respectively). Ghrelin at this dose had no effect on CCK-induced stimulation of c- fos expression in the paraventricular nucleus of the hypothalamus and the nucleus of the solitary tract. These results suggest that CCK abolishes ghrelin-induced food intake through dampening increased ARC neuronal acti