title: Acylation type determines ghrelin's effects on energy homeostasis in rodents.
abstract: Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin.
authors.affiliation: Metabolic Diseases Institute, Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Nilika
authors.initials: N
authors.lastname: Chaudhary
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: David L
authors.initials: DL
authors.lastname: Smiley
authors.forename: Richard
authors.initials: R
authors.lastname: Dimarchi
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Bjørn
authors.initials: B
authors.lastname: Sivertsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000215:Acylation; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D054439:Ghrelin / Q000378:metabolism* / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D054440:Receptors, Ghrelin / Q000235:genetics* / Q000378:metabolism
chemical_list: D054439:Ghrelin; D020033:Protein Isoforms; D054440:Receptors, Ghrelin