Various forms of fasting and ketogenic diet have shown promise in (pre-)clinical studies to normalize body weight, improve metabolic health, and protect against disease. Recent studies suggest that β-hydroxybutyrate (βOHB), a fasting-characteristic ketone body, potentially acts as a signaling molecule mediating its beneficial effects via histone deacetylase inhibition. Here, we have investigated whether βOHB, in comparison to the well-established histone deacetylase inhibitor butyrate, influences cellular differentiation and gene expression. In various cell lines and primary cell types, millimolar concentrations of βOHB did not alter differentiation in vitro, as determined by gene expression and histological assessment, whereas equimolar concentrations of butyrate consistently impaired differentiation. RNA sequencing revealed that unlike butyrate, βOHB minimally impacted gene expression in primary adipocytes, macrophages, and hepatocytes. However, in myocytes, βOHB up-regulated genes involved in the TCA cycle and oxidative phosphorylation, while down-regulating genes belonging to cytokine and chemokine signal transduction. Overall, our data do not support the notion that βOHB serves as a powerful signaling molecule regulating gene expression but suggest that βOHB may act as a niche signaling molecule in myocytes.

中文翻译：

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RNA测序揭示了β-羟基丁酸在初级肌管中的生态位基因表达效应。

各种形式的禁食和生酮饮食在（前）临床研究中显示出有望使体重正常化、改善代谢健康和预防疾病。最近的研究表明，β-羟基丁酸 (βOHB) 是一种具有禁食特征的酮体，它可能作为一种信号分子通过抑制组蛋白去乙酰化酶来介导其有益作用。在这里，我们研究了与成熟的组蛋白脱乙酰酶抑制剂丁酸盐相比，βOHB 是否影响细胞分化和基因表达。在各种细胞系和原代细胞类型中，通过基因表达和组织学评估确定，毫摩尔浓度的 βOHB 不会改变体外分化，而等摩尔浓度的丁酸盐始终会损害分化。RNA 测序显示，与丁酸盐不同，βOHB 对原代脂肪细胞、巨噬细胞和肝细胞中的基因表达影响最小。然而，在肌细胞中，βOHB 上调参与 TCA 循环和氧化磷酸化的基因，而下调属于细胞因子和趋化因子信号转导的基因。总体而言，我们的数据不支持βOHB 作为调节基因表达的强大信号分子的观点，但表明βOHB 可能作为肌细胞中的利基信号分子。