1323-OR: Zenagamtide Targets Key Feeding-Related Brain Regions and Induces Weight Loss by Preferentially Reducing Consumption of Unhealthy Solid and Liquid Diets in Rats

Introduction and Objective: An unhealthy diet is associated with obesity, cardiovascular disease and death. Zenagamtide (previously amycretin) is a novel unimolecular GLP1-, amylin- and calcitonin receptor agonist that decreased body weight by up to 24.3% in patients with obesity. As it is unknown if zenagamtide also promotes healthier food choices, we investigated zenagamtide’s distribution to feeding-related brain areas and how this affected dietary choices. Methods: Male Sprague Dawley rats were offered a free choice between healthy (chow + water) or unhealthy (chow / chocolate / peanut butter mix + fructose (10%) water) diets for 10 weeks. Rats were then treated with vehicle or zenagamtide (10 nmol/kg, SC, QD) for 3 weeks (n=11/grp). A chow + water group served as control (n=5). Another group of rats were injected IV with AF488/VT750-labelled zenagamtide (100 nmol/kg) or vehicle (n=6/grp) and brain distribution was analyzed by light-sheet microscopy or IHC. Results: Zenagamtide distributed to brain areas regulating food intake/preferences e.g., area postrema, arcuate nucleus and nucleus of the solitary tract. Zenagamtide targeted neuronal populations expressing the calcitonin receptor (core subunit of the amylin receptor), GLP1 receptor, or both indicating that zenagamtide works through both shared and distinct neuronal circuits. In free-choice rats, zenagamtide decreased body weight by -13% vs vehicle (p<0.001). Free-choice rats overconsumed fructose water and this overconsumption was reduced by -46% following zenagamtide treatment (p=0.0008). Zenagamtide reduced cumulative energy intake of unhealthy diet by -41% vs vehicle (p<0.0001) while chow intake was only nominally decreased (-10%, p=0.5729). Conclusion: Zenagamtide preferentially reduced intake of unhealthy diet and liquids in rats by targeting key brain regions regulating appetite and eating behavior. Thus, zenagamtide might promote a healthier diet in addition to weight loss in humans. Disclosure D. Ipsen: Employee; Current; Novo Nordisk A/S. A. Vegge: Employee; Current; Novo Nordisk. Stock/Shareholder; Current; Novo Nordisk, Zealand Pharma A/S. A. Secher: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Novo Nordisk A/S. K. Raun: Employee; Current; Novo Nordisk A/S. Stock/Shareholder; Current; Novo Nordisk A/S. S. Lundh: Employee; Current; Novo Nordisk A/S.