ABSTRACT
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 ß-hydroxybutyrate (ßOHB), a fasting-characteristic ketone body, potentially acts as a signaling molecule mediating its beneficial effects via histone deacetylase inhibition. Here, we have investigated whether ßOHB, 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 ßOHB 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, ßOHB minimally impacted gene expression in primary adipocytes, macrophages, and hepatocytes. However, in myocytes, ßOHB 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 ßOHB serves as a powerful signaling molecule regulating gene expression but suggest that ßOHB may act as a niche signaling molecule in myocytes.
