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In 1902, Ralph Larrabee provided intriguing evidence suggesting parallels between the changes in white blood cell counts observed in Boston Marathon runners and those seen in specific disease states. Notably he also noted a considerable leukocytosis of the inflammatory type, suggesting a potential link between extreme exercise and inflammatory responses. This early observation laid the groundwork for further investigations into the complex relationship between exercise intensity, immune system activation, and health outcomes, igniting an ongoing debate about the impact of exercise on the immune system.
Today we know exercise shows quantifiable and observable benefits to human health across multiple scales, but the specific genetic and biological processes and pathways underlying these benefits remain unclear. This is primarily caused by individuals exhibiting significant physiological variations in their response to exercise training, coupled with the diverse methods, subjects and timelines used in studying this phenomenon, which impacts the potential for clear and reproducible analysis. A deeper grasp of the metabolic and cellular impacts of exercise could lead to more targeted exercise approaches. Additionally, unraveling the molecular shifts induced by various exercise methods may hasten the identification of pharmaceutical targets for improving metabolic well-being. To combat the global pandemic of physical inactivity and its associated toll of 5.3 million deaths annually, we must gain a better understanding of the fundamental principles governing physical activity’s benefits.
Current Issue
Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice
Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice
Objective
Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass.
Methods
We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation.
Results
Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved.
Conclusion
Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.
Graphical abstract
Low dose glucagon agonism stimulates amino acid catabolism and lipid metabolism in liver. A high protein diet prevents the consequences of hypoaminoacidemia without affecting beneficial effects on MAFLD.
Articles in Press
Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice
Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice
Objective
Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass.
Methods
We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation.
Results
Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved.
Conclusion
Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.
Graphical abstract
Low dose glucagon agonism stimulates amino acid catabolism and lipid metabolism in liver. A high protein diet prevents the consequences of hypoaminoacidemia without affecting beneficial effects on MAFLD.
You are what you eat
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