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-PeredaKerstin Stemmer, Stephen C. Woods, Diego Perez-Tilve, Robert Schneider, Eric N. Olson, Matthias H. Tschöp, Paul T. Pfluger

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Article number10782
JournalNature communications
Volume7
DOIs
StatePublished - Feb 29 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Kabra, D. G., Pfuhlmann, K., García-Cáceres, C., Schriever, S. C., García, V. C., Kebede, A. F., Fuente-Martin, E., Trivedi, C., Heppner, K., Uhlenhaut, N. H., Legutko, B., Kabra, U. D., Gao, Y., Yi, C. X., Quarta, C., Clemmensen, C., Finan, B., Müller, T. D., Meyer, C. W., ... Pfluger, P. T. (2016). Hypothalamic leptin action is mediated by histone deacetylase 5. Nature communications, 7, [10782]. https://doi.org/10.1038/ncomms10782