2458-P: Arcuate Hypothalamic Circuits Mediate Acute Cagrilintide-Induced Feeding in Mice

Introduction and Objective: Cagrilintide is a long-acting amylin analogue currently in clinical development for the treatment of obesity, acting as a dual amylin and calcitonin receptor (CTR) agonist. While it produces robust body weight loss in humans, its effects are attenuated in mice, highlighting gaps in our understanding of its central mechanisms. Despite evidence for activity in multiple brain regions, the role of mouse mediobasal hypothalamic circuits in mediating cagrilintide’s effects remains largely unexplored. Methods: Therefore, we first assessed acute neuronal activation in CalcR-cre-tdTomato mice following acute cagrilintide administration (10 nmol/kg). Results: Cagrilintide increased cFos expression in CTR+ neurons of the arcuate nucleus (ARC) compared to vehicle, identifying the ARC as a potential direct target. Chemogenetic activation of ARC CTR+ neurons in CalcR-cre mice via hM3Dq induced a fast increase in food intake and body weight over two days, while chronic activation resulted in a transient hyperphagic response that normalized within seven days. This response may have been driven by AgRP activation as in situ hybridization revealed that approximately 60% of AgRP neurons and 40% of POMC neurons in the ARC co-express CTR, indicating engagement of key feeding circuits. To assess the necessity of ARC CTR+ neurons for cagrilintide’s anorectic effects, we selectively silenced CTR+ neurons in the ARC using a Cre-dependent tetanus toxin strategy. Silencing of these neurons impaired cagrilintide’s acute anorectic effect, as food intake was not significantly reduced on the first day of treatment compared to vehicle-treated Tetox mice. Notably, chronic cagrilintide reduced cumulative food intake in ARC CTR-silenced mice, indicating that these neurons are required only for the acute effect. Conclusion: Together, these findings define a mouse hypothalamic circuit engaged by cagrilintide and provide a framework to interpret species-specific differences in amylin receptor circuitry that may influence translational efficacy. Disclosure G. Lommi: Other - PhD student whose salary is paid by a Novo Nordisk grant; Current; Novo Nordisk. S. Vigolo: None. T.A. Lutz: Research Support; Current; Novo Nordisk. Consultant; Current; AbbVie Inc., Lilly, Zealand Pharma A/S, Roche Pharmaceuticals, Structure Tx. C. Le Foll: None.