1665-P: Whole-Brain Activation Signatures of Weight-Lowering Drugs

Background: The development of effective anti-obesity therapeutics relies heavily on the ability to target CNS signaling mechanisms critically involved in the homeostatic control of body weight. To get insight into neurocircuits recruited by anti-obesity drug treatment, the present study aimed to determine whole-brain activation signatures of six different weight-lowering drug classes with documented efficacy in humans. Methods: Chow-fed mice received a single dose of lorcaserin (7 mg/kg, i.p.), rimonabant (10 mg/kg, i.p.), bromocriptine (D2 receptor agonist, 10 mg/kg, i.p.), sibutramine (10 mg/kg, p.o.), semaglutide (0.04 mg/kg, s.c.) or setmelanotide (4 mg/kg, s.c.). Brains were sampled two hours post-dosing, immunolabelled using c-Fos expression as a proxy for neuronal stimulation. Cleared whole-brains were imaged using light sheet fluorescence microscopy-deep learning pipeline enabling fully automated 3D mapping and quantitation of brain activation patterns at single-cell resolution. Results: The whole-brain analysis comprised 308 atlas-defined mouse brain areas. To enable fast and efficient data mining, an open-access web-based 3D imaging data viewer (NeuroPedia.dk) was developed. All weight-lowering drugs demonstrated brain-wide responses with notable similarities in c-Fos expression signatures. Overlapping c-Fos responses were detected in discrete homeostatic and non-homeostatic feeding centres located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures as well as the dopaminergic system. Conclusion: We pinpoint several overlapping brain activation signatures of various weight-lowering drugs. This shared feature suggests that weight-lowering drugs stimulate distinct homeostatic and non-homeostatic feeding centres. Future centrally acting anti-obesity compounds may be specifically designed to target key components of this neurocircuitry framework to provide more effective and sustained weight loss in obese patients. Disclosure L.S.Dalboege: Employee; Gubra aps. J.Hecksher-sørensen: Employee; Gubra ApS. M.Tozzi: None. C.G.Salinas: Employee; Gubra. T.Porsgaard: Employee; Gubra. D.D.Thorbek: Employee; Gubra APS. J.L.Skytte: Employee; Gubra ApS. U.Roostalu: Employee; Gubra. H.H.Hansen: None. J.Perens: Employee; Gubra ApS.