Glucagon and energy expenditure; Revisiting amino acid metabolism and implications for weight loss therapy

Glucagon receptor (GCGR)-targeted multi-agonists are being developed for the treatment of obesity and metabolic disease. GCGR activity is utilised for its favourable weight loss and metabolic properties, including increased energy expenditure (EE) and hepatic lipid metabolism. GLP1R and GIPR activities are increasingly present in a multi-agonist strategy. Due to the compound effect of increased satiety, reduced food intake and increased energy expenditure, the striking weight loss effects of these multi-agonists has been demonstrated in pre-clinical models of obesity. The precise contribution and mechanism of GCGR activity to enhanced energy expenditure and weight loss in both rodents and humans is not fully understood. In this review, our understanding of glucagon-mediated EE is explored, and an amino acid-centric paradigm contributing to this phenomenon is presented. The current progress of GCGR-targeted multi-agonists in development is also highlighted with a focus on the implications of glucagon-stimulated hypoaminoacidemia.