Epigenetic imprinting of H3K4me3 in adipose-derived stem cells by HFS diet consumption leads to a disturbed transcriptomic profile in adipocytes [RNA-seq]

Adipose tissue metabolism is actively involved in the regulation of energy balance. Adipose-derived stem cells (ASCs) play a critical role in maintaining adipose tissue function through their differentiation into mature adipocytes. The aim of this study was to investigate the effect of an obesogenic environment on the epigenetic landscape of ASCs and its impact on adipocyte differentiation and its metabolic consequences. Our results showed that ASCs from mice fed a high-fat sucrose (HFS) diet exhibited reduced adipogenic capacity, increased fat accumulation, and formed larger adipocytes than those from the control group (C). The results showed that ASCs from mice fed the HFS diet had reduced adipogenic capacity. Mitochondrial analysis showed increased mitochondrial activity in undifferentiated ASC-HFS, but decreased respiratory and glycolytic capacity in mature adipocytes. The HFS diet significantly altered the H3K4me3 acetylation profile of ASCs in genes related to adipogenesis, mitochondrial function, inflammatory response and immunomodulation. After differentiation, adipocytes retained H3K4me3 alterations in genes related to inflammatory response and immunomodulation. RNA-seq confirmed the upregulation of genes associated with inflammatory and immunomodulatory pathways in adipocytes. This study demonstrates that HFS diet induces profound epigenetic and transcriptomic changes in ASCs, leading to impaired differentiation and dysfunctional adipocyte formation.脂肪组织代谢积极参与能量平衡的调控。脂肪源性干细胞（Adipose-derived stem cells, ASCs）可通过分化为成熟脂肪细胞，在维持脂肪组织功能中发挥关键作用。本研究旨在探究致肥胖环境对脂肪源性干细胞表观遗传景观的影响，及其对脂肪细胞分化与代谢结局的作用。本研究结果显示，与对照组（C组）小鼠来源的脂肪源性干细胞相比，喂食高糖高脂（high-fat sucrose, HFS）饮食的小鼠来源干细胞成脂能力降低、脂肪积累增多，且形成的脂肪细胞体积更大。前述结果亦证实，HFS饮食组小鼠来源的脂肪源性干细胞成脂能力降低。线粒体分析结果显示，未分化的HFS组脂肪源性干细胞线粒体活性升高，但成熟脂肪细胞的呼吸与糖酵解能力降低。HFS饮食可显著改变脂肪源性干细胞中与成脂作用、线粒体功能、炎症应答及免疫调节相关基因的组蛋白H3赖氨酸4三甲基化（H3K4me3）乙酰化谱。分化完成后，成熟脂肪细胞仍保留了与炎症应答及免疫调节相关基因的H3K4me3修饰改变。RNA测序（RNA-seq）证实，脂肪细胞中与炎症及免疫调节通路相关的基因表达上调。本研究表明，HFS饮食可在脂肪源性干细胞中诱导显著的表观遗传与转录组学改变，进而导致干细胞成脂能力受损以及功能异常的脂肪细胞生成。