Acylation type determines ghrelin's effects on energy homeostasis in rodents

Kristy Heppner; Nilika Chaudhary; Timo D Müller; Henriette Kirchner; Kirk M Habegger; Nickki Ottaway; David L Smiley; Richard Dimarchi; Susanna M Hofmann; Stephen C Woods; Bjørn Behrens Sivertsen; Birgitte Holst; Paul T Pfluger; Diego Perez-Tilve; Matthias H Tschöp

doi:10.1210/en.2012-1194

Acylation type determines ghrelin's effects on energy homeostasis in rodents

Kristy Heppner, Nilika Chaudhary, Timo D Müller, Henriette Kirchner, Kirk M Habegger, Nickki Ottaway, David L Smiley, Richard Dimarchi, Susanna M Hofmann, Stephen C Woods, Bjørn Behrens Sivertsen, Birgitte Holst, Paul T Pfluger, Diego Perez-Tilve, Matthias H Tschöp

Eyepath Lab

10 Citationer (Scopus)

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.

Originalsprog	Engelsk
Bogserie	Contemporary Endocrinology
Vol/bind	153
Udgave nummer	10
Sider (fra-til)	4687-95
Antal sider	9
ISSN	0196-8653
DOI	https://doi.org/10.1210/en.2012-1194
Status	Udgivet - 1 okt. 2012

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10.1210/en.2012-1194

Citationsformater

Heppner, K., Chaudhary, N., Müller, T. D., Kirchner, H., Habegger, K. M., Ottaway, N., Smiley, D. L., Dimarchi, R., Hofmann, S. M., Woods, S. C., Sivertsen, B. B., Holst, B., Pfluger, P. T., Perez-Tilve, D., & Tschöp, M. H. (2012). Acylation type determines ghrelin's effects on energy homeostasis in rodents. Contemporary Endocrinology, 153(10), 4687-95. https://doi.org/10.1210/en.2012-1194

Heppner, K, Chaudhary, N, Müller, TD, Kirchner, H, Habegger, KM, Ottaway, N, Smiley, DL, Dimarchi, R, Hofmann, SM, Woods, SC, Sivertsen, BB, Holst, B, Pfluger, PT, Perez-Tilve, D & Tschöp, MH 2012, 'Acylation type determines ghrelin's effects on energy homeostasis in rodents', Contemporary Endocrinology, bind 153, nr. 10, s. 4687-95. https://doi.org/10.1210/en.2012-1194

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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.",

keywords = "Acylation, Animals, Body Composition, Body Weight, Eating, Energy Metabolism, Ghrelin, Homeostasis, Male, Mice, Mice, Inbred C57BL, Protein Isoforms, Rats, Rats, Long-Evans, Receptors, Ghrelin",

author = "Kristy Heppner and Nilika Chaudhary and M{\"u}ller, {Timo D} and Henriette Kirchner and Habegger, {Kirk M} and Nickki Ottaway and Smiley, {David L} and Richard Dimarchi and Hofmann, {Susanna M} and Woods, {Stephen C} and Sivertsen, {Bj{\o}rn Behrens} and Birgitte Holst and Pfluger, {Paul T} and Diego Perez-Tilve and Tsch{\"o}p, {Matthias H}",

year = "2012",

month = oct,

day = "1",

doi = "10.1210/en.2012-1194",

language = "English",

volume = "153",

pages = "4687--95",

journal = "Contemporary Endocrinology",

issn = "0196-8653",

publisher = "Humana Press",

number = "10",

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TY - JOUR

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 - 2012/10/1

Y1 - 2012/10/1

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

SN - 0196-8653

VL - 153

SP - 4687

EP - 4695

JO - Contemporary Endocrinology

JF - Contemporary Endocrinology

IS - 10

ER -

Acylation type determines ghrelin's effects on energy homeostasis in rodents

Abstract

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