Role of histone deacetylase 3 (HDAC3) in adipose tissue metabolism and immunophenotype: Selected Abstract - SITeCS Congress 2022

L. Coppi, C. Peri, F. Bonacina, R. Longo, Dalma Cricrí, S. Pedretti, Rui Silva, I. Severi, A. Giordano, G. Norata, A. Catapano, N. Mitro, E. De Fabiani, M. Crestani
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Abstract

Introduction: Obesity is associated with comorbidities such as cardiovascular disease and type 2 diabetes. HDAC3 regulates adipose tissue physiology (WAT), and its genetic inactivation causes metabolic reprogramming of white adipocytes toward browning. The aim of this work is to evaluate the effect of HDAC3 silencing at different stages of differentiation and investigate the influence of adipocyte metabolism on the immunophenotype of WAT. Materials and Methods: Following HDAC3 silencing in mesenchymal stem cells and mature adipocytes, adipocyte function, RNA, DNA and protein levels, and proliferation at the end of differentiation were analyzed. Visceral WAT immunophenotype (vWAT) of Hdac3 KO mice in WAT (Hdac3fatKO) and controls (FL) was performed by FACS. Results: Silencing HDAC3 in precursors amplifies the expression of genes and proteins that regulate differentiation, oxidative metabolism, browning and mitochondrial activity. Following silencing, we found increased 1)phosphorylation of AKT (1.64 fold change, P<0.0001), indicative of increased insulin signaling, and 2)proliferation, characteristic of the early phase of differentiation. Mitochondrial content was unchanged, but increased mitochondrial activity was observed in terms of maximal respiration (1.42 fold change, P=0.0151) and uncoupling of the electron transport chain (+11.6%, P<0.0001). No difference was observed following HDAC3 silencing in mature adipocytes. We hypothesized that the enhancement of oxidative metabolism may cause cellular damage or senescence and, consequently, the immunophenotype of vWAT might be affected by HDAC3 ablation. Analysis reveals an increase of macrophages (2.48 fold change, P=0.0311) in the vWAT of Hdac3fatKO mice polarizing toward the M2 population. Coculture of adipocytes with macrophages from bone marrow indicates that HDAC3 silencing in adipocytes stimulates macrophage activation. Conclusions: HDAC3 is a key factor in the WAT phenotype, and its inactivation triggers mechanisms that support browning. Early epigenetic events mediated by HDAC3 silencing are crucial in directing adipocyte precursors toward the oxidative phenotype. Finally, results obtained from ex vivo and in vitro studies suggest that specific factors produced by KO adipocytes may be involved in determining the observed immunophenotype. [FONDAZIONE CARIPLO 2015-0641]
组蛋白去乙酰化酶3 (HDAC3)在脂肪组织代谢和免疫表型中的作用:精选摘要- SITeCS大会2022
肥胖与合并症有关,如心血管疾病和2型糖尿病。HDAC3调节脂肪组织生理(WAT),其基因失活导致白色脂肪细胞向褐化方向代谢重编程。本研究旨在评价HDAC3沉默在不同分化阶段的作用,探讨脂肪细胞代谢对WAT免疫表型的影响。材料与方法:对间充质干细胞和成熟脂肪细胞中HDAC3沉默后的脂肪细胞功能、RNA、DNA和蛋白水平以及分化末期的增殖情况进行分析。采用流式细胞仪测定WAT (Hdac3fatKO)和对照组(FL) Hdac3 KO小鼠内脏WAT免疫表型(vWAT)。结果:沉默HDAC3前体可扩增调节分化、氧化代谢、褐变和线粒体活性的基因和蛋白的表达。沉默后,我们发现1)AKT磷酸化增加(1.64倍变化,P<0.0001),表明胰岛素信号传导增加;2)增殖,分化早期的特征。线粒体含量没有变化,但线粒体活性在最大呼吸(1.42倍变化,P=0.0151)和电子传递链解偶联(+11.6%,P<0.0001)方面有所增加。在成熟脂肪细胞中,HDAC3沉默后未观察到差异。我们假设氧化代谢的增强可能导致细胞损伤或衰老,因此,HDAC3消融可能会影响vWAT的免疫表型。分析显示,Hdac3fatKO小鼠向M2群体极化时,vWAT中巨噬细胞增加(变化2.48倍,P=0.0311)。脂肪细胞与骨髓巨噬细胞共培养表明,脂肪细胞中HDAC3的沉默刺激巨噬细胞的激活。结论:HDAC3是WAT表型的关键因子,其失活触发支持褐变的机制。由HDAC3沉默介导的早期表观遗传事件是指导脂肪细胞前体向氧化表型的关键。最后,离体和体外研究结果表明,KO脂肪细胞产生的特定因子可能参与了观察到的免疫表型的决定。[fondazione cariplo 2015-0641]
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