Abstract
Glucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues.
Highlights
Glucagon receptor agonists show promise as components of generation metabolic syndrome pharmacotherapies
To study the effects of sustained glucagon receptor (GCGR) activation, we developed a glucagon analogue (GCG104) through modification of OXM with the aim of reducing its glucagon-like peptide-1 receptor (GLP-1R) activity and decreasing its rate of clearance
In vitro assessment of this molecule demonstrated that its potency at the mouse GCGR is similar to that of native glucagon (Fig. 1b)
Summary
Glucagon receptor agonists show promise as components of generation metabolic syndrome pharmacotherapies. It has allowed us to make two important observations about the biology of sustained GCGR agonism It causes weight loss in mice by direct receptor signalling at the level of the liver. Subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters Together, these findings confirm the liver as a principal target for glucagonmediated weight loss and provide new insights into the biology of glucagon analogues. Several bioactive peptides which include GCGR agonism as a deliberate component of their pharmacodynamic profile are being developed which show promise for the treatment of metabolic syndromes in humans[10,11,12] In many cases these act as functional analogues of oxyntomodulin (OXM), which stimulates the glucagon-like peptide-1 receptor (GLP-1R) to maximise weight loss and augment insulin secretion[13]. Our findings highlight the importance of considering agonist dose and sensitivity, both in mechanistic studies and potential clinical applications of glucagon receptor agonists
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