期刊
NATURE METABOLISM
卷 3, 期 8, 页码 1071-1090出版社
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00432-5
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资金
- Agence National de la Recherche [ANR-15-CE14-0025, ANR-17-CE14-0034]
- European Research Council (ERC Synergy Grant WATCH) [810331]
- National Institutes of Health (NIH) [R01DK123002]
- European Genomic Institute for Diabetes (EGID) [ANR-10-LABX-0046]
- DISTALZ [ANR-11-LABX-0009]
- I-SITE ULNE [ANR-16-IDEX-0004]
- Who am I? [ANR-11-LABX-0071]
- DHU Autoimmune and Hormonal Diseases
- European Foundation for the Study of Diabetes
- Universite de Lille
- Fondation pour la Recherche Medicale
- H2020-MSCA-IF-2016 grant GLUCOTANYCYTES [748134]
- European Research Council (ERC) [810331] Funding Source: European Research Council (ERC)
The expression of leptin receptors in tanycytes is crucial for leptin to enter the brain and regulate peripheral lipogenesis and pancreatic beta-cell function. Tanycytic transport of leptin through LepRb-EGFR may also be important in the pathophysiology of diabetes.
Duquenne et al. show that tanycyte leptin receptor expression is required for leptin to enter the brain and regulate peripheral lipogenesis and pancreatic beta-cell function. 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 beta-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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