The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats.

BACKGROUND: Amycretin is a novel unimolecular glucagon-like peptide-1 (GLP-1) and amylin receptor agonist. This study aimed to determine its role in mitigating diet-induced metabolic disorders, such as obesity, insulin resistance, and fatty liver disease, in mice and rats. METHODS: Preclinical studies were conducted to characterise amycretin activation of GLP-1, amylin and calcitonin receptors, and determine the effects of amycretin administration on the metabolic health of mice and rats. Investigations included measurements of body weight and body composition, energy intake and energy expenditure, insulin sensitivity, metabolic dysfunction-associated steatotic liver disease (MASLD), and access in the mouse brain. FINDINGS: Amycretin activated human, mouse and rat GLP-1, amylin and calcitonin receptors in cell-based systems. In diet-induced obese (DIO) rats, amycretin administration for 21 days reduced total energy intake by 47% (95% CI (mean), kcal: vehicle: 2132-2493 vs. amycretin: 1044-1390) and lowered body weight by 18% (95% CI (mean), % change relative to pre-treatment: vehicle: 6.56-8.47 vs. amycretin: -10.48 to -12.74, p < 0.0001), while maintaining energy expenditure. Amycretin targeted key areas of the mouse brain that regulate food intake. Insulin sensitivity improved significantly with amycretin administration in DIO rats compared with vehicle controls, shown by higher glucose infusion rates during a hyperinsulinaemic euglycemic clamp. Additionally, amycretin improved histological hallmarks of MASLD, primarily by reducing steatosis. INTERPRETATION: Amycretin had various beneficial effects on metabolic health in mice and rats; effectively reducing body weight, enhancing insulin sensitivity, and improving MASLD activity scores. Thus, amycretin could be a promising therapeutic option for metabolic diseases including obesity and type 2 diabetes, warranting further clinical trials assessing its efficacy in humans. FUNDING: Novo Nordisk A/S.