DVC Gatekeeping of Incretin Receptor Agonist therapies

Objective

New anti-obesity drugs targeting incretin receptors (IRAs) offer the first safe and effective anti-obesity treatments. However, their long-term benefit is limited by high discontinuation rates due to major intestinal side effects. IRAs suppress appetite by signalling in the brain, but due to their large size, they only access aversive circuits of the hindbrain and fail to diffuse to hindbrain regions supporting non-aversive satiety. Access to these deeper regions is restricted by the Funiculus Separens (FS), a poorly characterised diffusion barrier. I hypothesise that the FS gates diffusion of IRAs to deeper hindbrain regions and determines whether IRAs recruit aversive rather than non-aversive appetite-suppressing circuits. I will use an interdisciplinary multi-omics approach to deliver the first molecular, cellular, structural and functional map of the FS. I will test how obesity and IRAs remodel FS structure and function, integrating behaviour, in vivo recordings, and whole-brain c-Fos mapping in lean and diet-induced obese mice. Finally, I will establish causality between FS function and behavioural responses to IRAs. For this project, I bring expertise in the gut–brain axis, glial and brainstem neurobiology, brain surgery and behavioural phenotyping. The host institution will provide state-of-the-art core facilities (genomics, imaging, proteomics, neurotechnology), supervision in nutrient sensing, IRA mechanisms and ECM biology, and structured training (spatial transcriptomics, proteomics, image analysis, tissue clearing, fibre photometry, leadership). The project will produce open, reusable assets (standard operating procedures, analysis code, datasets) and advance multi-omics and multiplexed 3D imaging in metabolic neuroscience. Longer term, the framework extends to other circulating peptides with aversive components, informing better-tolerated therapies and enabling cross-disciplinary links with oncology/cachexia, maternal health, and gastroenterology.