Hypothalamic leptin action is mediated by histone deacetylase 5

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. Henriette Uhlenhaut, Beata Legutko, Uma D. Kabra, Yuanqing Gao, Chun-Xia Yi, Carmelo Quarta, Christoffer Clemmensen, Brian Finan, Timo D. Müller, Carola W. Meyer, Marcelo Paez-Pereda, Kerstin Stemmer, Stephen C. Woods, Diego Perez-Tilve, Robert Schneider, Eric N. Olson, Matthias H. Tschöp () and Paul T. Pfluger
Additional contact information
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
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
Chitrang Trivedi: Zydus Research Centre, Cadila Healthcare Limited
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
Uma D. Kabra: Helmholtz Diabetes Center, Helmholtz Zentrum München
Yuanqing Gao: Helmholtz Diabetes Center, Helmholtz Zentrum 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
Paul T. Pfluger: Helmholtz Diabetes Center, Helmholtz Zentrum München

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10782

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DOI: 10.1038/ncomms10782

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