Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism

Abstract

Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism.. Molecular and Cellular Endocrinology, Elsevier, 2011, 335 (2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 37A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2 ABSTRACT Ghrelin, a hormone whose levels increase during food deprivation, plays a pivotal role in the regulation of food intake, energy metabolism and storage, as well as in insulin sensitivity. Here, we investigated the effects of acyl-ghrelin neutralization with the acyl-ghrelin-binding compound NOX-B11(2) during the fasting-refeeding cycle. Our data demonstrate that ghrelin neutralization with NOX-B11(2) impairs recuperation of lost body weight after food deprivation. Analysis of enzymes involved in glucose and lipid metabolism in liver of fed, fasted and refed rats revealed that neutralization of acyl-ghrelin resulted in minor decreases in the enzymes of glycolytic and lipogenic pathways during fasting. However, during refeeding these enzymes as well as glycogen levels recovered more slowly when acyl-ghrelin was blocked. The high levels of ghrelin in response to food deprivation may contribute to an adequate decrease in hepatic glycolytic and lipogenic enzymes and aid in the recovery of body weight and energetic reserves once food becomes available after the fasting period.

Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases

“…8) and laboratory rats (food intake; Ref. 58). SPM-triggered increases in circulating acylated ghrelin concentrations also have been previously shown in diet-induced obese mice receiving chronic infusions of SPM (33 mg·kg Ϫ1 ·day Ϫ1 ) that led to weight loss and reduced food intake (59) and in food-deprived rats injected intraperitoneally with SPM (30 mg/kg, every 24 h) that thwarted full recuperation of body weight with refeeding (58).…”

“…The apparent inability of SPM to block the food deprivation-induced increases in food hoarding and c-Fos-ir might be interpreted as ghrelin not being necessary for the increases in this appetitive ingestive behavior after food withdrawal-refeeding. Because, however, it was previously shown that SPM-treated laboratory mice and rats had circulating acylated ghrelin concentrations ϳ10 times that of controls (58,59) and food deprivation-induced c-Fos-ir was not inhibited (8), we tested whether a possible compensatory increase in circulating acylated ghrelin may have overcome the SPM-induced neutralization, thereby obfuscating this test of ghrelin necessity. Therefore, we assayed both acylated and des-acyl circulating ghrelin in SPM-and vehicle-treated hamsters that were ad libitum-fed or 48 h food-deprived, as in the behavioral tests.…”

“…Others speculated that the rise of plasma acylated ghrelin with SPM treatment can be explained by a compensatory increase in ghrelin synthesis, a prolonged halflife and/or decreased clearance rate of the peptide when bound to SPM, or a combination of all of the above (43, 44). Becskei et al (8) and Sangiao-Alvarellos et al (58) argued that ghrelin might not be necessary for food deprivation-triggered increases Different letters indicate statistical differences P Ͻ 0.05. B: control wells run in tandem with A of 3.6 mg/ml SPM, 18 pg/ml des-acyl ghrelin, or 3.6 mg/ml SPM ϩ 9 pg/ml des-acyl ghrelin (note the initial des-acyl ghrelin concentrations).…”

“…58). SPM-triggered increases in circulating acylated ghrelin concentrations also have been previously shown in diet-induced obese mice receiving chronic infusions of SPM (33 mg·kg Ϫ1 ·day Ϫ1 ) that led to weight loss and reduced food intake (59) and in food-deprived rats injected intraperitoneally with SPM (30 mg/kg, every 24 h) that thwarted full recuperation of body weight with refeeding (58). The increase in circulating acylated ghrelin concentrations of these latter two studies was, however, of a lesser magnitude than seen here, and des-acyl ghrelin concentrations were not assessed (58, 59).…”

“…This overlooked another possibility suggested by the increased ghrelin concentrations assayed (58,59)-that the ghrelin assay recognized acylated ghrelin bound to SPM and/or unbound SPM. Therefore, to more completely test the necessity of ghrelin in food-deprived animals with specific regard to the circulating concentrations of ghrelin, we obtained a separate cohort of male Siberian hamsters (n ϭ 24) from our breeding colony.…”