3033-LB: Spatiocellular Mapping Indicates Complementary Action of Amylin and GLP-1 Receptor Agonism in the Human Brain

Introduction and Objective: Dual targeting of amylin and GLP1 receptors (e.g., CagriSema or zenagamtide) promotes greater weight loss than either mono component alone. This complementary effect on appetite and energy intake is thought to be mediated by engagement of specific brain pathways in the hypothalamus and hindbrain. To extend this research into humans and inform dual targeting strategies, we mapped and compared the spatial and cellular expression profiles of amylin and GLP1 receptor components in human and rodent brains. Methods: We performed multimodal profiling using snRNA-seq, spatial transcriptomics, ISH and IHC on human post-mortem hypothalamus and hindbrain tissue (n=7-10), focusing on amylin receptor components (CALCR and RAMPs), GLP1R and key cell markers. For comparison, we analyzed rodent snRNA-seq data and performed ISH/IHC on rodent samples (n=12) to assess spatial and cellular similarities. Results: GLP1- and amylin receptor-expressing cells mainly showed non-overlapping cellular profiles in the hypothalamus and hindbrain. Comparisons to rodents revealed broad conservation of receptor-expressing cell types, but also differences in abundance and co-expression patterns (e.g., with POMC/AGRP and RAMPs). In the hindbrain, expression of CALCR differed from GLP1R in neuronal populations associated with aversive behavior. Conclusion: Detailed spatiocellular mapping demonstrates that while GLP1 and amylin receptor systems are present in conserved appetite-regulating brain regions they are primarily expressed in distinct cell populations. The data supports the translational relevance of preclinical models while highlighting areas where human-specific receptor distribution may influence pharmacology and mechanism-of-action. Complementary receptor expression in human brain support the clinical significance in targeting both biological pathways in parallel with CagriSema/zenagamtide and may suggest a favourable nausea and vomiting profile for amylin agonists (e.g. cagrilintide). Disclosure M.Q. Ludwig: Employee; Current; Novo Nordisk A/S. S. Bau: Employee; Current; Novo Nordisk A/S. G. Dowsett: None. L. Steuernagel: Research Support; Current; Novo Nordisk A/S. G. Yeo: Research Support; Ended; Novo Nordisk A/S. Research Support; Current; Amgen Inc. Consultant; Current; Eli Lilly and Company, Novo Nordisk 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.