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 OryRalf Jockers, Markus Schwaninger, Ulrich Boehm, Ruben Nogueiras, Jean-Sébastien Annicotte, Stéphane Gasman, Julie Dam, Vincent Prévot


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.

Original languageEnglish
JournalNature metabolism
Issue number8
Pages (from-to)1071-1090
Number of pages20
Publication statusPublished - 08.2021


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