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Hypothalamic leptin action is mediated by histone deacetylase 5

Author

Listed:
  • Dhiraj G. Kabra

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Katrin Pfuhlmann

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Cristina García-Cáceres

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Sonja C. Schriever

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Veronica Casquero García

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Adam Fiseha Kebede

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg)

  • Esther Fuente-Martin

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Chitrang Trivedi

    (Zydus Research Centre, Cadila Healthcare Limited
    Metabolic Diseases Institute, University of Cincinnati)

  • Kristy Heppner

    (Metabolic Diseases Institute, University of Cincinnati)

  • N. Henriette Uhlenhaut

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Beata Legutko

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Uma D. Kabra

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Yuanqing Gao

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Chun-Xia Yi

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Carmelo Quarta

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Christoffer Clemmensen

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Brian Finan

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Timo D. Müller

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Carola W. Meyer

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Marcelo Paez-Pereda

    (Max Planck Institute of Psychiatry)

  • Kerstin Stemmer

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

  • Stephen C. Woods

    (Metabolic Diseases Institute, University of Cincinnati)

  • Diego Perez-Tilve

    (Metabolic Diseases Institute, University of Cincinnati)

  • Robert Schneider

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg)

  • Eric N. Olson

    (UT Southwestern Medical Center)

  • Matthias H. Tschöp

    (Helmholtz Diabetes Center, Helmholtz Zentrum München
    Technische Universität München)

  • Paul T. Pfluger

    (Helmholtz Diabetes Center, Helmholtz Zentrum München)

Abstract

Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment.

Suggested Citation

  • Dhiraj G. Kabra & Katrin Pfuhlmann & Cristina García-Cáceres & Sonja C. Schriever & Veronica Casquero García & Adam Fiseha Kebede & Esther Fuente-Martin & Chitrang Trivedi & Kristy Heppner & N. Henrie, 2016. "Hypothalamic leptin action is mediated by histone deacetylase 5," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10782
    DOI: 10.1038/ncomms10782
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    Cited by:

    1. Laia Guardia-Escote & Jordi Blanco & Pia Basaure & Judit Biosca-Brull & Rikst Nynke Verkaik-Schakel & Maria Cabré & Fiona Peris-Sampedro & Cristian Pérez-Fernández & Fernando Sánchez-Santed & Torsten , 2020. "Sex and Exposure to Postnatal Chlorpyrifos Influence the Epigenetics of Feeding-Related Genes in a Transgenic APOE Mouse Model: Long-Term Implications on Body Weight after a High-Fat Diet," IJERPH, MDPI, vol. 18(1), pages 1-17, December.
    2. Stéphane Leon & Vincent Simon & Thomas H. Lee & Lukas Steuernagel & Samantha Clark & Nasim Biglari & Thierry Lesté-Lasserre & Nathalie Dupuy & Astrid Cannich & Luigi Bellocchio & Philippe Zizzari & Ca, 2024. "Single cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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