In vivo characterization of high Basal signaling from the ghrelin receptor

Pia Steen Petersen; David P D Woldbye; Andreas Nygaard Madsen; Kristoffer L Egerod; Chunyu Jin; Manja Lang; Maria Rasmussen; Annette G Beck-Sickinger; Birgitte Holst

doi:10.1210/en.2008-1638

In vivo characterization of high Basal signaling from the ghrelin receptor

Pia Steen Petersen, David P D Woldbye, Andreas Nygaard Madsen, Kristoffer L Egerod, Chunyu Jin, Manja Lang, Maria Rasmussen, Annette G Beck-Sickinger, Birgitte Holst

84 Citations (Scopus)

Abstract

The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution. Food intake and body weight were significantly decreased in the group of rats treated with the inverse agonist, as compared with the groups treated with the control peptide or the vehicle. In the hypothalamus, the expression of neuropeptide Y and uncoupling protein 2 was decreased by the inverse agonist. In a hypothalamic cell line that endogenously expresses the ghrelin receptor, we observed high basal activity of the cAMP response element binding protein, an important signaling transduction pathway for appetite regulation. The activation was further increased by ghrelin administration and decreased by administration of the inverse agonist. It is suggested that the high constitutive signaling activity is important for the in vivo function of the ghrelin receptor in the control of food intake and body weight.

Original language	English
Journal	Endocrinology
Volume	150
Issue number	11
Pages (from-to)	4920-30
Number of pages	10
ISSN	0013-7227
DOIs	https://doi.org/10.1210/en.2008-1638
Publication status	Published - 2009

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10.1210/en.2008-1638

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@article{b50e8580883b11df928f000ea68e967b,

title = "In vivo characterization of high Basal signaling from the ghrelin receptor",

abstract = "The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution. Food intake and body weight were significantly decreased in the group of rats treated with the inverse agonist, as compared with the groups treated with the control peptide or the vehicle. In the hypothalamus, the expression of neuropeptide Y and uncoupling protein 2 was decreased by the inverse agonist. In a hypothalamic cell line that endogenously expresses the ghrelin receptor, we observed high basal activity of the cAMP response element binding protein, an important signaling transduction pathway for appetite regulation. The activation was further increased by ghrelin administration and decreased by administration of the inverse agonist. It is suggested that the high constitutive signaling activity is important for the in vivo function of the ghrelin receptor in the control of food intake and body weight.",

author = "Petersen, {Pia Steen} and Woldbye, {David P D} and Madsen, {Andreas Nygaard} and Egerod, {Kristoffer L} and Chunyu Jin and Manja Lang and Maria Rasmussen and Beck-Sickinger, {Annette G} and Birgitte Holst",

note = "Keywords: Animals; Body Weight; Eating; Gene Expression; Hyperphagia; Hypothalamus; Ion Channels; Male; Mitochondrial Proteins; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Ghrelin; Signal Transduction; Streptozocin; Up-Regulation",

year = "2009",

doi = "10.1210/en.2008-1638",

language = "English",

volume = "150",

pages = "4920--30",

journal = "Endocrinology",

issn = "0013-7227",

publisher = "Oxford University Press",

number = "11",

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TY - JOUR

T1 - In vivo characterization of high Basal signaling from the ghrelin receptor

AU - Petersen, Pia Steen

AU - Woldbye, David P D

AU - Madsen, Andreas Nygaard

AU - Egerod, Kristoffer L

AU - Jin, Chunyu

AU - Lang, Manja

AU - Rasmussen, Maria

AU - Beck-Sickinger, Annette G

AU - Holst, Birgitte

N1 - Keywords: Animals; Body Weight; Eating; Gene Expression; Hyperphagia; Hypothalamus; Ion Channels; Male; Mitochondrial Proteins; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Ghrelin; Signal Transduction; Streptozocin; Up-Regulation

PY - 2009

Y1 - 2009

N2 - The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution. Food intake and body weight were significantly decreased in the group of rats treated with the inverse agonist, as compared with the groups treated with the control peptide or the vehicle. In the hypothalamus, the expression of neuropeptide Y and uncoupling protein 2 was decreased by the inverse agonist. In a hypothalamic cell line that endogenously expresses the ghrelin receptor, we observed high basal activity of the cAMP response element binding protein, an important signaling transduction pathway for appetite regulation. The activation was further increased by ghrelin administration and decreased by administration of the inverse agonist. It is suggested that the high constitutive signaling activity is important for the in vivo function of the ghrelin receptor in the control of food intake and body weight.

AB - The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution. Food intake and body weight were significantly decreased in the group of rats treated with the inverse agonist, as compared with the groups treated with the control peptide or the vehicle. In the hypothalamus, the expression of neuropeptide Y and uncoupling protein 2 was decreased by the inverse agonist. In a hypothalamic cell line that endogenously expresses the ghrelin receptor, we observed high basal activity of the cAMP response element binding protein, an important signaling transduction pathway for appetite regulation. The activation was further increased by ghrelin administration and decreased by administration of the inverse agonist. It is suggested that the high constitutive signaling activity is important for the in vivo function of the ghrelin receptor in the control of food intake and body weight.

U2 - 10.1210/en.2008-1638

DO - 10.1210/en.2008-1638

M3 - Journal article

C2 - 19819980

SN - 0013-7227

VL - 150

SP - 4920

EP - 4930

JO - Endocrinology

JF - Endocrinology

IS - 11

ER -

In vivo characterization of high Basal signaling from the ghrelin receptor

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