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Leptin brain entry via a tanycytic LepR–EGFR shuttle controls lipid metabolism and pancreas function

Nature Metabolism volume 3, pages 1071–1090 (2021)Cite this article

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Abstract

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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Fig. 1: Tanycytes of the ME express functional leptin receptors.
Fig. 2: Tanycytic EGFR physically interacts with LepR in vivo and plays a role in leptin trancytosis in vitro.
Fig. 3: Selective LepR deletion in tanycytes causes food-intake-independent body weight gain and increased adiposity.
Fig. 4: Defective LepR and EGFR signalling in tanycytes causes hypothalamic resistance to circulating leptin.
Fig. 5: Selective LepR deletion in tanycytes causes hyperlipidaemia and steatosis.
Fig. 6: Loss of LepR expression in ME tanycytes causes severe pancreatic β-cell dysfunction, possibly due to defective noradrenaline activity.
Fig. 7: Loss of LepR expression in ME tanycytes alters adrenergic receptor expression in the pancreas and impairs cold-mediated increases in noradrenaline.

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Data availability

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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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Cintia Folgueira, Cyril Bourouh, Marion Millet, Anisia Silva, Jérôme Clasadonte.

  2. These authors jointly supervised this work: Stéphane Gasman, Julie Dam, Vincent Prévot.

Authors and Affiliations

  1. Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France

    Manon Duquenne, Jérôme Clasadonte, Monica Imbernon, Daniela Fernandois, Ines Martinez-Corral, Emilie Caron, S. Rasika, Eleonora Deliglia, Nathalie Jouy & Vincent Prévot

  2. Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

    Cintia Folgueira & Ruben Nogueiras

  3. CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain

    Cintia Folgueira

  4. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1283-UMR 8199-EGID, Lille, France

    Cyril Bourouh & Jean-Sébastien Annicotte

  5. Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France

    Marion Millet, Stéphane Ory & Stéphane Gasman

  6. Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France

    Anisia Silva, Asturo Oishi, Ralf Jockers & Julie Dam

  7. Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany

    Soumya Kusumakshi & Ulrich Boehm

  8. Flow Cytometry Core Facility, BioImaging Center of Lille, Hospital Campus, UMS2014-US41, Lille, France

    Nathalie Jouy

  9. Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Department of Oncology, Leuven, Belgium

    Massimiliano Mazzone

  10. Cisbio Bioassays, Parc Technologique Marcel Boiteux, Codolet, France

    Eric Trinquet

  11. VIB-UGent Center for Medical Biotechnology, Gent, Belgium

    Jan Tavernier

  12. Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Young-Bum Kim

  13. Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany

    Markus Schwaninger

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  1. Manon Duquenne
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  2. Cintia Folgueira
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Contributions

M.D., C.F., C.B., M. Millet, A.S., J.C., M.I., D.F., I.M.-C., S.K., E.C., E.D., N.J., A.O. and S.O. carried out the experiments. M. Mazzone, J.T., E.T., M.S., S.K. and U.B. generated tools, vectors and animal models. Y.-B.K., R.J., M.S., U.B., R.N., J.-S.A., S.G., J.D. and V.P. designed and planned the study. All authors discussed the results, and M.D., S.R., S.G., J.D. and V.P. wrote the manuscript.

Corresponding author

Correspondence to Vincent Prévot.

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Competing interests

The authors declare no competing interests.

Additional information

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.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–7, and Tables 1 and 2

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Source data

Source Data Fig. 1

Uncropped immunoblot images.

Source Data Fig. 2

Uncropped immunoblot images.

Source Data Fig. 2

List of upstream activated tyrosine kinases and differential phosphorylated peptides in tanycytes treated with PBS or leptin for 2 min. Related to Fig. 2f.

Source Data Fig. 5

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

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