Ferrari Alessandra, Longo Raffaella, Fiorino Erika, Silva Rui, Mitro Nico, Cermenati Gaia, Gilardi Federica, Desvergne Béatrice, Andolfo Annapaola, Magagnotti Cinzia, Caruso Donatella, Fabiani Emma De, Hiebert Scott W, Crestani Maurizio
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, 20133, Italy.
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Nat Commun. 2017 Jul 21;8(1):93. doi: 10.1038/s41467-017-00182-7.
White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
白色脂肪组织（WAT）可响应寒冷等环境刺激而发生表型转换，即褐变。组蛋白的翻译后修饰已被证明可调节细胞能量代谢，但其在白色脂肪组织生理学中的作用仍未完全了解。在此我们表明，组蛋白去乙酰化酶3（HDAC3）调节白色脂肪组织的代谢和功能。脂肪中Hdac3的选择性缺失通过激活脂肪酸从头合成和β-氧化的无效循环来改变白色脂肪组织的代谢特征，该循环增强了白色脂肪组织的氧化能力并最终支持褐变。脂肪组织中Hdac3的特异性缺失增加了Pparg和Ucp1基因中增强子以及Ppara基因假定调控区域的乙酰化。我们的结果揭示HDAC3是白色脂肪组织生理学的调节因子，它作为一种分子制动器抑制脂肪酸代谢和白色脂肪组织褐变。诸如HDAC3之类的组蛋白去乙酰化酶已被证明可改变各种组织中的细胞代谢。在此，作者表明HDAC3通过激活脂肪酸合成与氧化的无效循环来调节白色脂肪组织的代谢，该循环支持白色脂肪组织褐变。
