Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats
Aims: To investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats. Background: Oxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and i...
Main Authors: | , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2015-12-01
|
Series: | Current Therapeutic Research |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0011393X15000156 |
id |
doaj-aaa18885f69b45769062c34a97fd582d |
---|---|
record_format |
Article |
spelling |
doaj-aaa18885f69b45769062c34a97fd582d2020-11-24T22:35:51ZengElsevierCurrent Therapeutic Research0011-393X1879-03132015-12-0177C11111510.1016/j.curtheres.2015.10.003Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar RatsSamantha L. Price, MResJames S. Minnion, PhDStephen R. Bloom, MDAims: To investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats. Background: Oxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity. The effects of Glu-3 OXM analogues have not been investigated in rats. Methods: The effect of 2 Glu-3-substituted OXM-like analogues (eg, OXM14E3 and OXM15E3) on food intake and body weight was investigated in male Wistar rats during 6 days of daily subcutaneous (SC) administration. The effects of Glu-3 substitution on analogue binding and activity at the rat GCGr and rat GLP-1 receptor were investigated in vitro using Chinese hamster ovary or Chinese hamster lung cells. Results: We report the novel finding that 2 5-nmol/kg Glu-3 OXM-like analogues (OXM14E3 and OXM15E3) significantly increased rat body weight by up to 4% compared with the equivalent non-Glu-3 analogues (OXM14 and OXM15), without affecting food intake. The effect of OXM15E3 on body weight was dose–dependent. Glu-3 analogues, including Glu-3 OXM, decreased glucagon-mediated cyclic adenosine monophosphate accumulation in Chinese hamster ovary cells expressing the rat GCGr, suggesting they may be acting as antagonists. Conclusions: The results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight.http://www.sciencedirect.com/science/article/pii/S0011393X15000156analoguebody weightglucagonsoxyntomodulin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Samantha L. Price, MRes James S. Minnion, PhD Stephen R. Bloom, MD |
spellingShingle |
Samantha L. Price, MRes James S. Minnion, PhD Stephen R. Bloom, MD Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats Current Therapeutic Research analogue body weight glucagons oxyntomodulin |
author_facet |
Samantha L. Price, MRes James S. Minnion, PhD Stephen R. Bloom, MD |
author_sort |
Samantha L. Price, MRes |
title |
Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats |
title_short |
Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats |
title_full |
Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats |
title_fullStr |
Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats |
title_full_unstemmed |
Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats |
title_sort |
investigating the glucagon receptor and glucagon-like peptide 1 receptor activity of oxyntomodulin-like analogues in male wistar rats |
publisher |
Elsevier |
series |
Current Therapeutic Research |
issn |
0011-393X 1879-0313 |
publishDate |
2015-12-01 |
description |
Aims: To investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats.
Background: Oxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity. The effects of Glu-3 OXM analogues have not been investigated in rats.
Methods: The effect of 2 Glu-3-substituted OXM-like analogues (eg, OXM14E3 and OXM15E3) on food intake and body weight was investigated in male Wistar rats during 6 days of daily subcutaneous (SC) administration. The effects of Glu-3 substitution on analogue binding and activity at the rat GCGr and rat GLP-1 receptor were investigated in vitro using Chinese hamster ovary or Chinese hamster lung cells.
Results: We report the novel finding that 2 5-nmol/kg Glu-3 OXM-like analogues (OXM14E3 and OXM15E3) significantly increased rat body weight by up to 4% compared with the equivalent non-Glu-3 analogues (OXM14 and OXM15), without affecting food intake. The effect of OXM15E3 on body weight was dose–dependent. Glu-3 analogues, including Glu-3 OXM, decreased glucagon-mediated cyclic adenosine monophosphate accumulation in Chinese hamster ovary cells expressing the rat GCGr, suggesting they may be acting as antagonists.
Conclusions: The results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight. |
topic |
analogue body weight glucagons oxyntomodulin |
url |
http://www.sciencedirect.com/science/article/pii/S0011393X15000156 |
work_keys_str_mv |
AT samanthalpricemres investigatingtheglucagonreceptorandglucagonlikepeptide1receptoractivityofoxyntomodulinlikeanaloguesinmalewistarrats AT jamessminnionphd investigatingtheglucagonreceptorandglucagonlikepeptide1receptoractivityofoxyntomodulinlikeanaloguesinmalewistarrats AT stephenrbloommd investigatingtheglucagonreceptorandglucagonlikepeptide1receptoractivityofoxyntomodulinlikeanaloguesinmalewistarrats |
_version_ |
1725722699707187200 |