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Kabra, D.G. ; Pfuhlmann, K. ; García-Cáceres, C. ; Schriever, S.C. ; Casquero García, V. ; 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. ; Paez-Pereda, M.* ; Stemmer, K. ; Woods, S.C.* ; Perez-Tilve, D.* ; Schneider, R.* ; Olson, E.N.* ; Tschöp, M.H. ; Pfluger, P.T.

Hypothalamic leptin action is mediated by histone deacetylase 5.

Nat. Commun. 7:10782 (2016)
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Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Green Fluorescent Protein; Nervous-system Control; Insulin-resistance; Proopiomelanocortin Neurons; Glucose-homeostasis; Physical-activity; Gene-expression; Deficient Mice; Pomc Neurons; Obesity
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 7, Issue: , Pages: , Article Number: 10782 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed