277-LB: LRP1 Mediates the Transport of Leptin Across the Blood-CSF Barrier at the Choroid Plexus

Leptin is an adipocyte-derived hormone that reduces food intake and stimulates energy expenditure. In order to achieve its physiological actions, it needs to enter the brain. The precise routes of brain entry of many metabolic signals have not been identified, but most studies suggest that transport across the BBB and CSF barrier are required. This study was designed to test the hypothesis that LRP1 mediates leptin’s transport across the blood-CSF barrier at the choroid plexus (ChP). To address this, we have first generated Foxj1-Cre; tdTomato mice to see the expression pattern of Foxj1 in the brain. The expression of tdTomato is restricted to the epithelial cells of the ChP and the ependymal cells of the ventricles. Mice lacking LRP1 in the epithelial cells and ependymal cells of the brain were thus generated and studied. Here we show that deletion of LRP1 in the epithelial cells of the ChP and the ependymal cells of the ventricles causes hyperleptinemia. This effect is independent of body weight and adiposity. In addition, mice lacking LRP1 in the epithelial cells of the ChP and the ependymal cells of the ventricles are insulin-resistant. Most importantly, leptin-induced food intake and hypothalamic Stat3 phosphorylation were significantly impaired in Foxj1-Cre; LRP1^lox/lox mice compared with LRP1^lox/lox mice. However, ICV leptin decreased food intake and increased hypothalamic Stat3 phosphorylation in Foxj1-Cre; LRP1^lox/lox mice. There were no differences in both food intake and Stat3 phosphorylation between LRP1^lox/lox mice and Foxj1-Cre; LRP1^lox/lox mice. These data clearly demonstrate that LRP1 in the epithelial cells of the ChP mediates leptin transport across the blood-CSF barrier at the ChP and further implicate that defective leptin transport may not contribute to the regulation of body weight homeostasis.