Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice

Vagal afferent neurons (VAN) express the cholecystokinin (CCK) type 1 receptor (CCK(1)R) and, as predicted by the role of CCK in inducing satiation, CCK(1)R-/- mice ingest larger and longer meals. However, after a short fast, CCK(1)R-/- mice ingesting high fat (HF) diets initiate feeding earlier than wild-type mice. We hypothesized that the increased drive to eat in CCK(1)R-/- mice eating HF diet is mediated by ghrelin, a gut peptide that stimulates food intake. The decrease in time to first meal, and the increase in meal size and duration in CCK(1)R-/- compared to wild-type mice ingesting high fat (HF) diet were reversed by administration of GHSR1a antagonist D-(Lys3)-GHRP-6 (p<0.05). Administration of the GHSR1a antagonist significantly increased expression of the neuropeptide cocaine and amphetamine-regulated transcript (CART) in VAN of HF-fed CCK(1)R-/- but not wild-type mice. Administration of the GHSR1a antagonist decreased neuronal activity measured by immunoreactivity for fos protein in the nucleus of the solitary tract (NTS) and the arcuate nucleus of both HF-fed wild-type and CCK(1)R-/- mice. The data show that hyperphagia in CCK(1)R-/- mice ingesting HF diet is reversed by blockade of the ghrelin receptor, suggesting that in the absence of the CCK(1)R, there is an increased ghrelin-dependent drive to feed. The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK(1)R-/- mice. (C) 2011 Elsevier Inc. All rights reserved.