Background: GLP-1/glucagon dual agonists are being developed as treatments for obesity due to their combined effect of reducing food intake while increase energy expenditure. Though the effect of the dual agonist on carbohydrate and lipid metabolism is well studied, little is known about the effects on protein metabolism. This study aimed to examine the acute and chronic effects of the GLP-1/glucagon dual agonist on amino acid metabolism.
Methods: The long-acting GLP-1/glucagon dual agonist analogue, OX-SR, or a vehicle control, was administered to male Wistar rats either as a single dose (n=8), or as a daily dose for 22 days as part of a pair-feeding paradigm (n=9). Plasma, liver and muscle samples were taken 4 h after the single injection, and 24 h after the final injection in the chronic study. Plasma amino acids were measured and qPCR of hepatic urea cycle enzymes Argininosuccinate Synthetase (Ass) and Carbamoyl Phosphate Synthetase (Cps) as well as muscle-specific E3 ubiquitin ligase enzymes Atrogin-1 and MuRF-1 were undertaken. Urine volume and urea concentration measured over the last 16 h of the chronic study.
Results: Both acutely and chronically, OX-SR significantly reduced plasma amino acids independently of food intake. There was also a significant increase in the hepatic urea cycle enzymes at both time points. Acutely, OX-SR did not effect on muscle-specific ligases; chronically there was an elevation in both Atrogin-1 and MuRF-1. In the chronic study, there was a non-significant increase urine output and total urinary urea excretion.
Conclusions: This data suggests that the GLP-1/glucagon dual agonist, OX-SR enhances hepatic uptake of amino acids with subsequent deamination to urea, in vivo. Chronically, there is also degradation of muscle proteins to sustain these changes. Further investigation in to the effect of these analogues in humans is required.