Project Summary The overall goal of this grant is to elucidate the physiologic, cellular, and molecular mechanism(s) underlying leptin resistance in obesity-linked metabolic disorders and, in particular, how circulating leptin is delivered into the brain, with the long-term goal of finding new therapeutic targets for obesity. Leptin is secreted by adipocytes to regulate food intake and body weight. In order to achieve its physiological actions, it needs to enter the brain. In obesity, circulating leptin levels are elevated but the ratio of CSF to plasma leptin is decreased, and leptin only suppresses food intake when administered centrally but not peripherally, suggesting that impaired leptin transport into the brain could be a mechanism for leptin resistance during the development of obesity. However, significant gaps in understanding leptin’s function in energy balance have been the lack of knowledge regarding how adipocyte-derived leptin gain access to the hypothalamic neurons. We now have preliminary data showing LRP1 or LRP2 (low-density lipoprotein receptor-related protein-1 or -2) functions as a potential leptin transporter that can deliver circulating leptin into the brain through the choroid plexus or tanycytes. We found that deletion of LRP1 in the epithelial cells of the choroid plexus impairs food intake when leptin is administered peripherally. However, centrally administered leptin decreases food intake in mice lacking LRP1 in the epithelial cells of the choroid plexus. Interestingly, LRP2 is enriched in hypothalamic tanycytes but is not expressed in the neurons of the arcuate nucleus of the hypothalamus (ARH). Deletion of LRP2 in the hypothalamic area, including tanycytes, causes severe obesity and impairs leptin action on food intake. We thus hypothesize that LRP1 mediates the transport of leptin across the blood-CSF barrier at the choroid plexus, while LRP2 transports leptin from the CSF to ARH neurons via tanycytes. In this grant, Aim 1 will establish the physiological role of LRP1 in regulating leptin transport in the choroid plexus. Aim 2 will elucidate the physiological role of LRP2 in the leptin transport system in hypothalamic tanycytes. Aim 3 will determine the biological function of LRP2 in the delivery of leptin by tanycytes of the ARH. To accomplish this, our work will employ a tour de force of state-of-the-art biochemical, molecular, cellular, and physiological techniques to understand the dynamic sensing of leptin by the brain, and its impacts on energy metabolism. These studies provide a unique opportunity to establish a new paradigm in which LRP 1 and LRP2 are key determinants of leptin-mediated metabolism and may offer a novel target for the treatment of obesity.