1539-P: LRP1 Mediates Leptin Transport by Coupling with the Short-Form Leptin Receptor in the Choroid Plexus

Leptin is an adipocyte-derived satiety factor that suppresses food intake and increases energy expenditure by reaching anorexigenic neurons in the brain. While leptin typically interacts with the leptin receptor (LepR), evidence reveals a high binding affinity of leptin to the choroid plexus (ChP), a distinct brain barrier that mediates peripheral-brain signal communication, in LepR-deficient db/db mice and obese Zucker rats. This suggests that the ChP may be a major site for leptin transport through specific receptors other than LepR. Here, we show that LRP1 (low-density-lipoprotein receptor-related protein-1) transports leptin across the blood-CSF barrier in Foxj1-expressing cells highly enriched at the ChP. LRP1 deletion in Foxj1-expressing cells of the ChP leads to impaired leptin transport, resulting in leptin resistance and obesity. Mechanistically, we found that LRP1 is associated with the short-form leptin receptor, LepRa, a crucial step for leptin entry into the brain. In vitro study with ChP-derived Z310 epithelial cells demonstrated that leptin rapidly stimulated a ~1.8-fold increase in LRP1 internalization over control conditions but failed to induce LRP1 internalization in the absence of LepRa, suggesting LepRa is required for leptin-induced LRP1 internalization. Notably, leptin-induced LRP1 binding to LepRa is attenuated in the ChP of diet-induced obese mice, highlighting the pathophysiological relevance of this interaction. Our findings unravel a new cellular mechanism by which LRP1 functions as a key mediator of leptin delivery for maintaining metabolic homeostasis in energy intake.