New research examines the effects of glucagon receptor-targeted drugs, which are being developed for the treatment of obesity and metabolic disease.

Glucagon receptor-targeted drugs have been shown to improve fatty liver disease, blood glucose and weight loss. The new study, led by researchers in Imperial's Department of Metabolism, Digestion and Reproduction and published in Cell Reports Medicine, found that in mice, a long-acting drug targeting the glucagon receptor leads to an increased breakdown of amino acids in the liver with implications for whole-body metabolism.

"We are excited to be able to present findings that provide further insight into the biology of glucagon, which may inform its use as a pharmacotherapeutic for obesity and metabolic disease." Dr David Hope Clinical Research Fellow, Department of Metabolism, Digestion and Reproduction

They found that the lowering of amino acids in response to glucagon is a cause of increased energy expenditure and body weight loss, and this is prevented with a high protein diet. Furthermore, although the breakdown of amino acids is associated with muscle loss and weakening of strength, the researchers found that increasing the low circulating amino acids with a high protein diet helps to reduce muscle loss. Therefore, it is hoped that this may provide a safe way to deliver drugs that activate the glucagon receptor.

The team's findings also suggest that with the high protein diet, glucagon receptor-targeted drugs are still able to improve fatty liver and blood glucose control. These findings can now be used to guide the development of glucagon-receptor-targeted drugs to help improve fatty liver disease and blood glucose control.

Understanding breakdown of amino acids in the liver

A key physiological action of glucagon is the breakdown of amino acids in the liver. However, the whole-body implications of amino acid breakdown in response to a glucagon receptor-targeted drug are unclear. This research addresses these challenges and, in particular, our understanding of how glucagon receptor-targeted drugs may increase energy expenditure and contribute towards weight loss. The research shows that low amino acid availability in response to glucagon is a mechanism of enhanced energy expenditure and weight loss.

The research also seeks to understand the long-term effects of glucagon receptor-targeted drugs on plasma amino acids and lean mass/muscle. It shows that low amino acids and lean mass loss in response to glucagon therapy can be mitigated with a high-protein diet. Currently, glucagon receptor-targeted drugs are in early-phase clinical trials for obesity and metabolic disease, however, their effect on lean mass in humans is not clear. It will therefore be important to determine their long-term effects on amino acid metabolism in humans, and the implications of this for lean mass and energy expenditure.

Talking about the importance of the research, the first author and MRC Clinical Research Fellow in MDR, Dr David Hope said: "This year is the centenary year of the discovery of glucagon and yet many aspects of its biology are still being identified and described. We are excited to be able to present our findings which provide further insight into the biology of glucagon which may inform its use as a pharmacotherapeutic for obesity and metabolic disease.

"We believe that glucagon therapy can be optimised to leverage its multiple metabolic benefits, whilst avoiding excess amino acid breakdown which may lead to detrimental effects on lean mass. The future of gut hormone-based therapy for obesity and metabolic disease is exciting with many drugs currently being developed targeting multiple hormone receptors. This strategy has gained significant traction over the last decade due to the advantages of targeting several pathways regulating energy balance and glucose metabolism. Glucagon receptor activation will likely be an important part of a 'multi-agonist' strategy in the future and there is still a lot of exciting research to do in this area."

Implications for developing glucagon receptor-targeted drugs

Several glucagon receptor-targeted drugs are currently being developed for the treatment of obesity and metabolic disease. These show significant weight loss potential and metabolic benefits, in particular for fatty liver disease. However, a consequence of glucagon receptor activation by these drugs is an increase in breakdown of plasma amino acids.

These new findings show that this leads to increased loss of lean mass in a pre-clinical model of obesity, however, this effect can be blunted with a high-protein diet. This has implications for similar drugs in development, which may affect amino acids and lean mass and may benefit from concurrent dietary protein supplementation.

Furthermore, the findings demonstrate that low plasma amino acids provide an explanation for whole-body energy expenditure and body weight loss in response to glucagon therapy. Indeed, the precise mechanism(s) of glucagon-mediated energy expenditure has remained elusive and is likely multi-faceted.

Senior author, Professor Tricia Tan commented "In our model, the downstream energy-consuming pathways activated in response to low circulating amino acids are still unclear. Also, the contribution of low plasma amino acid availability to energy expenditure in humans in response to glucagon receptor targeted drugs is unknown and therefore requires further investigation."

Future research

The study was carried out in a pre-clinical model of obesity and therefore it will be important to determine whether the observations made will translate to humans. Currently, glucagon receptor-targeted drugs are in early phases of drug development (Phase 1/2). Therefore, the results are timely as they can be used to further explore the effects of these drugs on amino acid metabolism in humans and the wider implications of this. 

The team is planning to further investigate the whole-body effects of glucagon therapy in humans to determine strategies to optimise and leverage the multiple metabolic benefits this hormone can offer for the treatment of obesity and metabolic disease.

David C. D. Hope, Charlotte E. Hinds, Tatiana Lopes, Matthew L. Vincent, Jed V. Shrewsbury, Arthur T. C. Yu, Iona Davies, Rebecca Scott, Ben Jones, Kevin G. Murphy, James S. Minnion, Alessandro Sardini, David Carling, Thomas A. Lutz, Stephen R. Bloom, Tricia M. Tan, and Bryn M. Owen, Hypoaminoacidemia Underpins Glucagon-mediated Energy Expenditure and Weight Loss, 2022, Cell Reports Medicine, ISSN: 2666-3791