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Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin

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Abstract

Research on energy homeostasis has focused on neuronal signaling; however, the role of glial cells has remained little explored. Glial endozepines exert anorexigenic actions by mechanisms which remain poorly understood. In this context, the present study was designed to decipher the mechanisms underlying the anorexigenic action of endozepines and to investigate their potential curative effect on high-fat diet-induced obesity. We carried out a combination of physiological, pharmacological, and molecular analyses together to dissect the underlying mechanisms of endozepine-induced hypophagia. To evaluate the potential anti-obesity effect of endozepines, different model of obesity were used, i.e., ob/ob and diet-induced obese mice. We show that the intracerebral administration of endozepines enhances satiety by targeting anorexigenic brain circuitry and induces STAT3 phosphorylation, a hallmark of leptin signaling. Strikingly, endozepines are entirely ineffective at reducing food intake in the presence of a circulating leptin antagonist and in leptin-deficient mice (ob/ob) but potentiate the reduced food intake and weight loss induced by exogenous leptin administration in these animals. Endozepines reversed high fat diet-induced obesity by reducing food intake and restored leptin-induced STAT3 phosphorylation in the hypothalamus. Interestingly, we observed that glucose and insulin synergistically enhance tanycytic endozepine expression and release. Finally, endozepines, which induce ERK activation necessary for leptin transport into the brain in cultured tanycytes, require tanycytic leptin receptor expression to promote STAT3 phosphorylation in the hypothalamus. Our data identify endozepines as potential anti-obesity compounds in part through the modulation of the LepR-ERK-dependent tanycytic leptin shuttle.

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Funding

This work was supported by funding obtained from the Aix-Marseille Université, the Institut National de la Recherche Agronomique (INRA), the Institut National de la Santé et de la Recherche Médicale (Inserm), the Agence Nationale de la Recherche grant Glioshuttle4Metabolim (ANR-15-CE14-0025 to VP), and EZICROM (ANR-16-CE14-0011 to JL, VP, and JDT). The authors acknowledge Dr. S. Rasika for the editing of the manuscript and Coraline Airault, Catherine Tardivel, and Elise Courvoisier for their support in qPCR experiments (plateforme Analyse et Valorisation de la Biodiversité, Marseille). We also thank the Centre Pluridisciplinaire de Microscopie Electronique et de Microanalyse (CP2M, Aix-Marseille Université) for the access to their confocal microscopy equipment.

Author information

Author notes

  1. Florent Guillebaud and Manon Duquenne contributed equally to this work.

Authors and Affiliations

  1. CNRS UMR 7291, Laboratoire de Neurosciences Cognitives, Faculté des Sciences et Techniques de St Jérôme, Avenue Escadrille Normandie-Niemen, Université Aix-Marseille, 13397, Marseille cedex 20, France

    Florent Guillebaud, Mehdi Djelloul, Clément Pierre, Kevin Poirot, Guenièvre Roussel, André Jean, Stéphanie Gaigé, Bruno Lebrun, Michel Dallaporta & Jean-Denis Troadec

  2. INSERM U1172, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, Lille, France

    Manon Duquenne & Vincent Prevot

  3. School of Medicine, University of Lille, Lille, France

    Manon Duquenne & Vincent Prevot

  4. Biomeostasis CRO, La Penne sur Huveaune, Marseille, France

    Clément Pierre

  5. CNRS UMR UMR 7289, Institut des Neurosciences de la Timone, Université Aix-Marseille, Marseille, France

    Seddik Riad

  6. INSERM U1239, PRIMACEN, Laboratoire de Différenciation et Communication Neuronale et Neuroendocrine, Normandie Université, Rouen, France

    Damien Lanfray, Fabrice Morin, Marie-Christine Tonon & Jérôme Leprince

Authors
  1. Florent Guillebaud
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  2. Manon Duquenne
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  3. Mehdi Djelloul
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  4. Clément Pierre
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  5. Kevin Poirot
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  6. Guenièvre Roussel
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  7. Seddik Riad
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  8. Damien Lanfray
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  9. Fabrice Morin
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  10. André Jean
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  11. Marie-Christine Tonon
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  12. Stéphanie Gaigé
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  13. Bruno Lebrun
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  14. Michel Dallaporta
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  15. Jérôme Leprince
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  16. Vincent Prevot
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  17. Jean-Denis Troadec
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Contributions

FG, MD, MD, CP, GR, KP, SR, DL, SG, MD, and JL performed the experiments. JL contributed to the ODN and OP synthesis. FG, FM, AJ, MCT, SG, BL, MD, JL, VP, and JDT designed the study and analyzed the data. BL, JL, VP, and JDT wrote the manuscript.

Corresponding authors

Correspondence to Jérôme Leprince, Vincent Prevot or Jean-Denis Troadec.

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Conflict of Interest

FG is a fellow of the Nestlé France Foundation. CP is affiliated with Biomeostasis CRO. The other authors declare that they have no competing interests.

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Highlights

• Intracerebral administration of endozepines enhances satiety and induces STAT3 phosphorylation in the hypothalamus and brainstem.

• The anorexigenic action of endozepines requires a fully operative leptin signaling pathway.

• Endozepines reverse a diet-induced obese phenotype by reducing food intake.

• Leptin receptor expression into tanycytes is required for endozepine-induced STAT3 phosphorylation.

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Guillebaud, F., Duquenne, M., Djelloul, M. et al. Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin. Mol Neurobiol 57, 3307–3333 (2020). https://doi.org/10.1007/s12035-020-01944-z

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  • DOI: https://doi.org/10.1007/s12035-020-01944-z

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