title: Role of ghrelin in the relationship between hyperphagia and accelerated gastric emptying in diabetic mice.
abstract: OBJECTIVE
  Ghrelin is an orexigenic peptide with gastroprokinetic effects. Mice with streptozotocin (STZ)-induced diabetes exhibit hyperphagia, altered gastric emptying, and increased plasma ghrelin levels. We investigated the causative role of ghrelin herein by comparing changes in ghrelin receptor knockout (growth hormone secretagogue receptor [GHS-R](-/-)) and wild-type (GHS-R(+/+)) mice with STZ-induced diabetes.
  
  
  METHODS
  Gastric emptying was measured with the [(13)C]octanoic acid breath test. The messenger RNA (mRNA) expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), and proopiomelanocortin was quantified by real-time reverse-transcription polymerase chain reaction. Neural contractions were elicited by electrical field stimulation in fundic smooth muscle strips.
  
  
  RESULTS
  Diabetes increased plasma ghrelin levels to a similar extent in both genotypes. Hyperphagia was more pronounced in GHS-R(+/+) than in GHS-R(-/-) mice between days 12 and 21. Increases in NPY and AgRP mRNA expression were less pronounced in diabetic GHS-R(-/-) than in GHS-R(+/+) mice from day 15 on, whereas decreases in proopiomelanocortin mRNA levels were similar in both genotypes. Gastric emptying was accelerated to a similar extent in both genotypes, starting on day 16. In fundic smooth muscle strips of diabetic GHS-R(+/+) and GHS-R(-/-) mice, neuronal relaxations were reduced, whereas contractions were increased; this increase was related to an increased affinity of muscarinic and tachykinergic receptors.
  
  
  CONCLUSIONS
  Diabetic hyperphagia is regulated by central mechanisms in which the ghrelin-signaling pathway affects the expression of NPY and AgRP in the hypothalamus. The acceleration of gastric emptying, which is not affected by ghrelin signaling, is not the cause of diabetic hyperphagia and probably involves local contractility changes in the fundus.
authors.affiliation: Centre for Gastroenterological Research, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: Verhulst
authors.forename: Betty
authors.initials: B
authors.lastname: De Smet
authors.forename: Inge
authors.initials: I
authors.lastname: Saels
authors.forename: Theo
authors.initials: T
authors.lastname: Thijs
authors.forename: Luc
authors.initials: L
authors.lastname: Ver Donck
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.forename: Theo L
authors.initials: TL
authors.lastname: Peeters
authors.forename: Inge
authors.initials: I
authors.lastname: Depoortere
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D054369:Agouti-Related Protein / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D018678:Cholinergic Agents / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004435:Eating / Q000502:physiology; D005746:Gastric Emptying / Q000502:physiology*; D005748:Gastric Fundus / Q000294:innervation / Q000502:physiology; D054439:Ghrelin / Q000097:blood* / Q000235:genetics; D006963:Hyperphagia / Q000378:metabolism / Q000503:physiopathology*; D007031:Hypothalamus / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000235:genetics; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics* / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D001786:Blood Glucose; D018678:Cholinergic Agents; D054439:Ghrelin; D009478:Neuropeptide Y; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D013373:Substance P; D011333:Pro-Opiomelanocortin; D000109:Acetylcholine