CCK inhibits the orexigenic effect of peripheral ghrelin

Abstract

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 microg/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 microg/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 microg/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 microg/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 activity.

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

“…In fasted/refed mice, we also showed that ip urocortin 1 resulted in a 70-40% suppression over the 5-h post-injection consistent with previous reports [2,46]. Moreover, after obestatin administration (5 μmol/kg, ip) to freely fed rats, no effect on Fos expression pattern was observed in the PVN, ARC, VMH, DMH, and NTS while CCK-8S (1.75 nmol/kg, ip) increased Fos expression in the PVN, DMH, and NTS which is in agreement with previous studies [23,25].…”

“…p < 0.05 was considered significant. Semi-quantitative assessment of Fos-ir was achieved by counting the number of Fos-ir positive cells as described before [25]. Briefly, neurons with green nuclear staining were considered Fos-ir positive.…”

“…This contrast with most other gut peptides that influence feeding behavior by modulating neuronal activity in hypothalamic and brainstem nuclei. CCK-8S increases Fos expression in the PVN, DMH and NTS [23,25,29,33,38] while systemic or icv application of the long-term satiety signal leptin induces neuronal activation in PVN and DMH neurons [12,44], and peptide YY increases Fos expression in NTS, AP [6], and ARC [4]. Glucagonlike peptide 1 modulates the number of Fos-ir positive neurons in ARC [44], PVN, NTS and AP [28,39], and peripheral amylin leads to increased neuronal activation in the NTS and AP [39].…”

“…sulfated cholecystokinin octapeptide, CCK-8S, ghrelin, bombesin or amylin) are mediated at least partly by changes in neuronal activity in distinct brain nuclei [5,20,37,45]. For instance, specific brain pathways activated by intraperitoneally (ip) injected CCK-8S, as revealed by Fos-immunoreactivity (Fos-ir), include the paraventricular nucleus of the hypothalamus (PVN), the dorsomedial hypothalamic nucleus (DMH), the nucleus of the solitary tract (NTS) and the area postrema (AP) [23,25,29,33,38].…”

Ghrelin suppresses noradrenaline release in the brown adipose tissue of rats

“…Ghrelin increases Fos expression in the ventromedial nucleus, dorsomedial nucleus, suprachiasmatic nucleus, arcuate nucleus (ARC), and paraventricular nucleus (PVN) of the hypothalamus when administered i.c.v. or peripherally, and GHS-R1a is expressed in these nuclei (Lawrence et al 2002, Rüter et al 2003, Kobelt et al 2005, Mano-Otagiri et al 2006, Zigman et al 2006. The GHS-R1a expressed in GHRH neurons is mainly involved in ghrelin/GHS-induced GH secretion (Tannenbaum et al 2003).…”