Acylation type determines ghrelin's effects on energy homeostasis in rodents
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Acylation type determines ghrelin's effects on energy homeostasis in rodents. / Heppner, Kristy; Chaudhary, Nilika; Müller, Timo D; Kirchner, Henriette; Habegger, Kirk M; Ottaway, Nickki; Smiley, David L; Dimarchi, Richard; Hofmann, Susanna M; Woods, Stephen C; Sivertsen, Bjørn Behrens; Holst, Birgitte; Pfluger, Paul T; Perez-Tilve, Diego; Tschöp, Matthias H.
I: Contemporary Endocrinology, Bind 153, Nr. 10, 10.2012, s. 4687-95.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Acylation type determines ghrelin's effects on energy homeostasis in rodents
AU - Heppner, Kristy
AU - Chaudhary, Nilika
AU - Müller, Timo D
AU - Kirchner, Henriette
AU - Habegger, Kirk M
AU - Ottaway, Nickki
AU - Smiley, David L
AU - Dimarchi, Richard
AU - Hofmann, Susanna M
AU - Woods, Stephen C
AU - Sivertsen, Bjørn Behrens
AU - Holst, Birgitte
AU - Pfluger, Paul T
AU - Perez-Tilve, Diego
AU - Tschöp, Matthias H
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - Acylation
KW - Animals
KW - Body Composition
KW - Body Weight
KW - Eating
KW - Energy Metabolism
KW - Ghrelin
KW - Homeostasis
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Protein Isoforms
KW - Rats
KW - Rats, Long-Evans
KW - Receptors, Ghrelin
U2 - 10.1210/en.2012-1194
DO - 10.1210/en.2012-1194
M3 - Journal article
C2 - 22865372
VL - 153
SP - 4687
EP - 4695
JO - Contemporary Endocrinology
JF - Contemporary Endocrinology
SN - 0196-8653
IS - 10
ER -
ID: 46279971