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

Manon Duquenne, Cintia Folgueira, Cyril Bourouh, Marion Millet, Anisia Silva, Jérôme Clasadonte, Monica Imbernon, Daniela Fernandois, Ines Martinez-Corral, Soumya Kusumakshi, Emilie Caron, S Rasika, Eleonora Deliglia, Nathalie Jouy, Asturo Oishi, Massimiliano Mazzone, Eric Trinquet, Jan Tavernier, Young-Bum Kim, Stéphane Ory, Ralf Jockers, Markus Schwaninger, Ulrich Boehm, Ruben Nogueiras, Jean-Sébastien Annicotte, Stéphane Gasman, Julie Dam, Vincent Prévot

Journal: Nature metabolism 2021;3(8):1071-1090

PMID: 34341568

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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 Ca 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.

Address: Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France.; Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, CNRS, U1283-UMR 8199-EGID, Lille, France.; Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.; Institut Cochin, Inserm U1016, CNRS UMR 8104, University Paris Descartes, Sorbonne Paris Cité, Paris, France.; Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany.; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France.; Flow Cytometry Core Facility, BioImaging Center of Lille, Hospital Campus, UMS2014-US41, Lille, France.; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Department of Oncology, Leuven, Belgium.; Cisbio Bioassays, Parc Technologique Marcel Boiteux, Codolet, France.; VIB-UGent Center for Medical Biotechnology, Gent, Belgium.; Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.; Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.; Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S1172, EGID, DISTALZ, Lille, France. [email protected].

DOI: 10.1038/s42255-021-00432-5

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MeSH Terms: Brain, Diabetes Mellitus, Energy Metabolism, Ependymoglial Cells, ErbB Receptors, Insulin-Secreting Cells, Leptin, Lipid Metabolism, Pancreas, Phosphorylation, Receptors, Leptin