Circadian Transcriptomic and Epigenomic Remodeling in Response to Lipid Overload and Human Obesity

Abstract

ABSTRACTAims/hypothesisObesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms.MethodsWe determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from obese and normal weight men.ResultsPalmitate disrupted transcriptomic rhythmicity in myotubes. Genes that lost or gained rhythmicity after palmitate treatment were involved in metabolic processes, protein translation and transport, and transcriptional regulation. Histone H3K27ac, a marker of active gene enhancers, was modified by palmitate treatment in myotubes, but not in skeletal muscle from men with obesity.Conclusion/interpretationPalmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the epigenetic state of skeletal muscle. Our results indicate that dietary saturated fatty acids impart post-transcriptional modifications to histone proteins and regulate circadian transcriptomics.