Investigation of LRP1-mediated Choroid Plexus transcytosis of leptin to the CSF and modulation of the satiety-inducing effects of leptin on multiple downstream brain areas.
Molecular and Cellular Neurology and Neuropathology
Final Report Abstract
Obesity is a major global health crisis driven by complex interactions between peripheral metabolic signals and central appetite regulation. Leptin, a hormone secreted by fat cells, normally signals energy sufficiency and suppresses food intake. However, in diet-induced obesity (DIO), leptin resistance disrupts this feedback loop, leading to persistent overeating despite high leptin levels. This project began by investigating how leptin accesses the brain, focusing on the choroid plexus (ChP)— a key interface between blood and cerebrospinal fluid (CSF). However, at physiological doses, leptin remained undetectable in the CSF using existing methods. While this posed a technical challenge, it also created an opportunity to pivot toward a more tractable system. We redirected efforts to study hormonebrain communication using genetically encoded fluorescent biosensors for oxytocin (OXT), vasopressin (AVP), and serotonin (5-HT). These tools enabled reliable visualization of neuropeptides and monoamines in the CSF following both peripheral and central administration. This led to a key methodological advance: validating GRAB-AVP2.0, GRAB-OXT1.7, and GRAB-5-HT2hD as viable in vivo sensors for tracking neuroendocrine signals at the brain-CSF interface. These findings establish a valuable platform for developing CSF-based diagnostics and therapeutics, especially for neuroendocrine and neurodevelopmental disorders such as autism. In parallel, we explored how obesity affects central appetite regulation by recording activity in MC4R- expressing neurons in the paraventricular hypothalamus (PVH), key mediators of satiety. In DIO mice, these neurons showed disrupted satiety-linked activity, providing mechanistic insight into how high-fat diets impair central feeding signals and perpetuate metabolic dysfunction. Our findings reveal both structural and functional disruptions in hormone signaling under obesogenic conditions, underscoring the dual challenge of peripheral resistance and impaired central processing. Despite initial setbacks in leptin detection, the project successfully shifted to yield high-impact results - including novel hormone sensor validation, insights into ChP function, and new understanding of hypothalamic satiety circuits in obesity. Together, this work advances our understanding of the neuroendocrine basis of obesity and delivers critical tools and frameworks for future research. As interest in brain-based approaches to metabolic disease grows, these findings hold significant promise for both scientific and broader societal impact.
Publications
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Simultaneous, real-time tracking of many neuromodulatory signals with Multiplexed Optical Recording of Sensors on a micro-Endoscope. openRxiv.
Kalugin, Peter N.; Soden, Paul A.; Massengill, Crystian I.; Amsalem, Oren; Porniece, Marta; Guarino, Diana C.; Tingley, David; Zhang, Stephen X.; Benson, Jordan C.; Hammell, Madalon F.; Tong, David M.; Ausfahl, Charlotte D.; Lacey, Tiara E.; Courtney, Ya’el; Hochstetler, Alexandra; Lutas, Andrew; Wang, Huan; Geng, Lan; Li, Guochuan ... & Andermann, Mark L.
