Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats

Samantha L Price,James S Minnion,Stephen R Bloom

doi:10.1016/j.curtheres.2015.10.003

Samantha L Price, James S Minnion + Show 1 more

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https://doi.org/10.1016/j.curtheres.2015.10.003

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Abstract

AimsTo investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats. BackgroundOxyntomodulin (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. MethodsThe 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. ResultsWe 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. ConclusionsThe 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.

Highlights

The gut-derived hormone oxyntomodulin (OXM) is a naturally occurring dual agonist of both the glucagon receptor (GCGr) and glucagons-like peptide 1 receptor (GLP-1r).[1]
The dual agonist activity of OXM at the GCGr and GLP-1r makes it difficult to investigate the mechanisms involved in the weight-reducing effects of exogenous OXM administration because receptor antagonists block the actions of endogenous glucagon and GLP-1
It has been reported that exchanging the position-3 glutamine of OXM or a related analogue for Glu diminishes mouse GCGr activity without affecting activity at the mouse GLP-1r

Summary

Introduction

The gut-derived hormone oxyntomodulin (OXM) is a naturally occurring dual agonist of both the glucagon receptor (GCGr) and glucagons-like peptide 1 receptor (GLP-1r).[1] Structurally OXM is the 29 amino acids of glucagon with a C-terminal octapeptide tail.[2] Administration of OXM to rodents and humans reduces food intake and increases energy expenditure, generating significant weight loss and highlighting OXM as a potential pharmacologic treatment for obesity.[3,4] Due to the short in vivo half-life of native OXM,[5] it is necessary to produce long-lasting analogues for clinical use. The dual agonist properties of OXM make investigating its mechanism(s) of action difficult. Substituting glutamine at position 3 of OXM with Glu has previously been reported to diminish GCGr activity without affecting GLP-1r activity,[6,7] enabling investigation of mechanisms of action relating to exogenous OXM administration

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