Hypothalamic leptin action is mediated by histone deacetylase 5.
Hypothalamic leptin action is mediated by histone deacetylase 5.
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下丘脑瘦素作用是由组蛋白脱乙酰基酶5介导的。
DOI：
10.1038/ncomms10782
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发表时间：
2016-02-29
影响因子：
16.6
通讯作者：
Pfluger PT
中科院分区：
文献类型：
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作者：
Kabra DG;Pfuhlmann K;García-Cáceres C;Schriever SC;Casquero García V;Kebede AF;Fuente-Martin E;Trivedi C;Heppner K;Uhlenhaut NH;Legutko B;Kabra UD;Gao Y;Yi CX;Quarta C;Clemmensen C;Finan B;Müller TD;Meyer CW;Paez-Pereda M;Stemmer K;Woods SC;Perez-Tilve D;Schneider R;Olson EN;Tschöp MH;Pfluger PT
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. Histone deacetylases (HDACs) regulate energy metabolism in peripheral tissues, but whether HDACs expressed in the brain influence systemic metabolism is unknown. Here the authors show that hypothalamic HDAC5 expression is affected by the diet and HDAC5 regulates leptin sensitivity by deacetylating STAT3.
