title: Hypothalamic leptin action is mediated by histone deacetylase 5.
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.
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Dhiraj G
authors.initials: DG
authors.lastname: Kabra
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfuhlmann
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Cáceres
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Casquero García
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Adam Fiseha
authors.initials: AF
authors.lastname: Kebede
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Fuente-Martin
authors.affiliation: Department of Pharmacology &Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.|Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA.
authors.forename: Chitrang
authors.initials: C
authors.lastname: Trivedi
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Heppner
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Legutko
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Uma D
authors.initials: UD
authors.lastname: Kabra
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Quarta
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Clemmensen
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Carola W
authors.initials: CW
authors.lastname: Meyer
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 München, Germany.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pereda
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, Illkirch 67404, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.|Division of Metabolic Diseases, Technische Universität München, 80333 Munich, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Paul T
authors.identifier: http://orcid.org/0000-0002-8118-7588
authors.initials: PT
authors.lastname: Pfluger
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005951:Glucose Tolerance Test; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007333:Insulin Resistance; D061346:Laser Capture Microdissection; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D020738:Leptin; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases