Metabolic health depends on the brain’s ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR–EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic β-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb–EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.
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The Human Protein Reference Database (http://www.hprd.org) was used to identify upstream kinases in the PamGene assay. Uncropped immunoblots and source data files for PamGene analyses are provided as Extended data. Source data are provided with this paper. Additional data that support the findings of this study are available from the corresponding author upon request.
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This work was supported by Agence National de la Recherche (no. ANR-15-CE14-0025 to V.P., R.J. and S.G. and no. ANR-17-CE14-0034 to J.S.A.), the European Research Council (ERC Synergy Grant WATCH no. 810331 to V.P., R.N. and M.S.), the National Institutes of Health (NIH grant no. R01DK123002 to Y.-B.K. and V.P.), the European Genomic Institute for Diabetes (EGID, no. ANR-10-LABX-0046 to J.-S.A. and V.P.), DISTALZ (no. ANR-11-LABX-0009 to V.P.), I-SITE ULNE (no. ANR-16-IDEX-0004), ‘Who am I?’ (no. ANR-11-LABX-0071 to J.D.), DHU Autoimmune and Hormonal Diseases (Authors) (to J.D.), European Foundation for the Study of Diabetes (to J.-S.A.), Université de Lille (to M.D., C.B. and J.-S.A.), Fondation pour la Recherche Médicale (to M.D.) and the H2020-MSCA-IF-2016 grant GLUCOTANYCYTES (no. 748134 to M.I.). We thank L. Rolland for excellent technical help with immunofluorescence analysis of pancreatic sections, and R. Boutry and the UMR 8199 LIGAN-PM Genomic platform (EGID, no. ANR-10-EQPX-07-01) for Kinome assays. We thank UMS2014-US41 for technical support.
The authors declare no competing interests.
Peer review information Nature Metabolism thanks Marcelo Dietrich, John-Olov Jansson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Isabella Samuelson; Elena Bellafante.
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Uncropped immunoblot images.
Uncropped immunoblot images.
List of upstream activated tyrosine kinases and differential phosphorylated peptides in tanycytes treated with PBS or leptin for 2 min. Related to Fig. 2f.
Uncropped immunoblot images.
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Duquenne, M., Folgueira, C., Bourouh, C. et al. Leptin brain entry via a tanycytic LepR–EGFR shuttle controls lipid metabolism and pancreas function. Nat Metab 3, 1071–1090 (2021). https://doi.org/10.1038/s42255-021-00432-5