Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men

Abstract

. Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men. Am J Physiol Regul Integr Comp Physiol 292: R1391-R1399, 2007. First published November 30, 2006; doi:10.1152/ajpregu.00734.2006, peptide YY (PYY), and ghrelin have been proposed to act as satiety hormones. CCK and PYY are stimulated during meal intake by the presence of nutrients in the small intestine, especially fat, whereas ghrelin is inhibited by eating. The sequence of events (fat intake followed by fat hydrolysis and CCK release) suggests that this process is crucial for triggering the effects. The aim of this study was therefore to investigate whether CCK mediated the effect of intraduodenal (ID) fat on ghrelin secretion and PYY release via CCK-1 receptors. Thirty-six male volunteers were studied in three consecutive, randomized, double-blind, cross-over studies: 1) 12 subjects received an ID fat infusion with or without 120 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, compared with vehicle; 2) 12 subjects received ID long-chain fatty acids (LCF), ID medium-chain fatty acids (MCF), or ID vehicle; and 3) 12 subjects received ID LCF with and without the CCK-1 receptor antagonist dexloxiglumide (Dexlox) or ID vehicle plus intravenous saline (placebo). ID infusions were given for 180 min. The effects of these treatments on ghrelin concentrations and PYY release were quantified. Plasma hormone concentrations were measured in regular intervals by specific RIA systems. We found the following results. 1) ID fat induced a significant inhibition in ghrelin levels (P Ͻ 0.01) and a significant increase in PYY concentrations (P Ͻ 0.004). Inhibition of fat hydrolysis by orlistat abolished both effects. 2) LCF significantly inhibited ghrelin levels (P Ͻ 0.02) and stimulated PYY release (P Ͻ 0.008), whereas MCF were ineffective compared with controls. 3) Dexlox administration abolished the effect of LCF on ghrelin and on PYY. ID fat or LCF significantly stimulated plasma CCK (P Ͻ 0.006 and P Ͻ 0.004) compared with saline. MCF did not stimulate plasma CCK release. In summary, fat hydrolysis is essential to induce effects on ghrelin and PYY through the generation of LCF, whereas MCF are ineffective. Furthermore, LCF stimulated plasma CCK release, suggesting that peripheral CCK is the mediator of these actions. The CCK-1 receptor antagonist Dexlox abolished the effect of ID LCF, on both ghrelin and PYY. Generation of LCF through hydrolysis of fat is a critical step for fat-induced inhibition of ghrelin and stimulation of PYY in humans; the signal is mediated via CCK release and CCK-1 receptors. peptide YY; cholecystokinin THE PROCESS OF FOOD INTAKE is coordinated by interactions between the enteric nervous system and gastrointestinal hormones (34, 36). Many gastrointestinal hormones are released from specialized endocrine cells into the circulation or serve as neurotransmitters that mediate signals from the enteric nervous system. These signals are transmitted from the gut to the brain and become integrated at various centers ...

Gut chemosensing mechanisms

“…Ghrelin secretion is also inhibited by somatostatin, potentially involving SSTR1, -2, and -3 (48). The effects of other gut hormones on ghrelin release are varied (95)(96)(97). GIP, for example, has been reported as both an inhibitor and stimulator of ghrelin secretion.…”

Factors affecting circulating levels of peptide YY in humans: a comprehensive review

“…Appetite-suppressant effects of duodenal lipids are dependent on fat digestion, so fat digestion may also be a prerequisite for fat-induced stimulation of PYY (34) . Indeed, blocking the hydrolysis of long-chain fatty acids abolishes the typical PYY postprandial response, probably due to a lack of CCK release (29) . Other foods or substances have also been tested for potential PYY responses.…”

“…Because PYY release is affected by CCK levels (29) , it is possible that the effect of fatty acid composition on PYY is an indirect one through CCK. In the study mentioned above by Robertson et al (122) it was shown that peak CCK release after a high-fat meal challenge was greatest with a meal rich in SFA compared with either MUFA or PUFA.…”

Therapy for Obesity Based on Gastrointestinal Hormones

“…It stimulates gallbladder contraction and pancreatic enzyme secretion, and retards gastric emptying [82,83]. Furthermore, the release of PYY and GLP-1, after lipid ingestion, is dependent on signaling through the CCK receptor [84,85]. In the CNS, the gastrin receptor seems to be the main receptor; and the effects of CCK-8 and CCK-5 are probably mediated through this receptor as only trace amounts of gastrin are found in the CNS [80,86].…”