Introduction and Objective: The choroid plexus (ChP), located in each ventricle of the brain, is recognized as a potential site for leptin transport via short- and long-form leptin receptor (LepR). However, knowledge of how LepR in the ChP regulates leptin transport and energy metabolism remains limited. We investigated the role of LepR in Foxj1-expressing ChP cells in leptin transport and body weight regulation.Methods: Mice lacking LepR in Foxj1-expressing cells (Foxj1-Cre; LepRloxP/loxP) and LepRloxP/loxP mice were fed chow or high-fat diet (HFD). Foxj1 is enriched in ChP epithelial cells. We evaluated body weight, fat mass, serum hormones, food intake, leptin-stimulated food intake, and hypothalamic Stat3 phosphorylation. The interaction between LepR and LRP1 was measured by PLA. Leptin uptake and release were determined in cultured cell lines.Results: Foxj1-Cre-driven LepR deletion reduced LepR expression in ChP by ~80%. On a chow diet, deletion of LepR in Foxj1-expressing cells of the ChP modestly increased body weight and fat mass due to hyperphagia with elevated serum insulin and leptin but normal glucose. Importantly, leptin’s ability to suppress food intake and enhance hypothalamic pStat3 was significantly impaired in these mice. Under HFD, LepR deficiency further exacerbated weight gain and adiposity. Mechanistically, we found that leptin induces the physical interaction between LepR and LRP1 in the ChP. In vitro study demonstrated that leptin uptake and release were significantly reduced in ChP-derived Z310 epithelial cells lacking LepR. Conversely, LepR overexpression in Neuro-2a cells markedly increased leptin uptake and release.Conclusion: These findings suggest that LepR in Foxj1-expressing cells is required to regulate leptin transport, affecting feeding and body weight homeostasis. Thus, our study uncovers a new cellular mechanism in which LepR in the ChP functions as a key mediator of leptin transport, maintaining metabolic homeostasis.
K. Rodrigues: None. W. Yang: None. J. Young: None. M. Lee: None. F. Timzoura: None. V. Prevot: None. Y. Kim: None.
American Diabetes Association (1-25-PDF-49); RO1DK1230023RO1DK129946-03
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