ABSTRACT
Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a "Dessert Effect" protocol in which the intake of a palatable high fat diet "dessert" was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.
Subject(s)
Acyltransferases/physiology , Feeding Behavior/physiology , Ghrelin/metabolism , Acylation/physiology , Acyltransferases/genetics , Acyltransferases/metabolism , Animals , Appetite Regulation/drug effects , Appetite Regulation/genetics , Appetite Regulation/physiology , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Weight/drug effects , Body Weight/physiology , Feeding Behavior/drug effects , Ghrelin/blood , Ghrelin/pharmacology , Ghrelin/physiology , Intracellular Signaling Peptides and Proteins/blood , Intracellular Signaling Peptides and Proteins/metabolism , Male , Membrane Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Motivation/drug effects , Motivation/genetics , Motivation/physiology , Neuropeptides/blood , Neuropeptides/metabolism , OrexinsABSTRACT
UNLABELLED: Systemic ghrelin concentration falls rapidly after nutrient ingestion in vivo. The effect incretins on ghrelin secretion in humans remains unclear. We quantified circulating ghrelin concentrations under hyperglycemic conditions combined with infusion of gastric inhibitory polypeptide (GIP) and arginine. METHODS: Eight healthy volunteers were studied with a hyperglycemic clamp followed by addition of GIP (2 pmol.kg(-1).min(-1), 60-115 min) and an arginine-bolus and -infusion (10 mg.kg(-1).min(-1), 90-115 min). RESULTS: Hyperglycemia alone increased circulating insulin concentrations (p<0.01), and decreased ghrelin concentrations to 89.8% of basal (p=0.208). GIP-infusion resulted in circulating insulin concentration of 1109+/-942 pmol/l (p<0.02) and no further decrease of ghrelin (86.2% of baseline, p=0.050). Under arginine- and GIP-infusion together, insulin concentrations increased progressively to 3005+/-1604 pmol/l (p<0.01) without further decreasing in ghrelin concentrations (98.9% of baseline, p=0.575). CONCLUSIONS: Hyperglycemic hyperinsulinemia and further increases of hyperinsulinemia to supraphysiological and high supraphysiological concentrations under GIP- and arginine-infusion do not significantly decrease ghrelin concentrations in healthy subjects. Moreover, there is no dose-dependent suppression of ghrelin by insulin in the hyperglycemic condition. Neither GIP nor arginine affected ghrelin release.
Subject(s)
Arginine/metabolism , Gastric Inhibitory Polypeptide/metabolism , Hyperglycemia/metabolism , Peptide Hormones/blood , Adult , Arginine/administration & dosage , Female , Gastric Inhibitory Polypeptide/administration & dosage , Ghrelin , Glucose Clamp Technique , Humans , Insulin/blood , MaleABSTRACT
Beta-adrenergics have recently come in the focus of clinical, physiological, and pharmacological research. The side-effects of tocolytically active substances are under thorough study at present. The authors checked the laboratory values recorded from 45 patients in pregnancy. Electrocardiographic follow-up checks were also conducted, with the view to establishing the effects of Dilatol and Partusisten on both the electrolyte balance and myocardium.--The results are described and discussed, and conclusions are suggested.