Diurnal regulation of whole-body lipid metabolism plays a vital role in metabolic health. Although changes in lipid levels across the diurnal cycle have been investigated, the system-wide molecular responses to both short-acting fasting-feeding transitions and longer-timescale circadian rhythms have not been explored in parallel. Here, we perform time-series multi-omics analyses of liver and plasma revealing that the majority of molecular oscillations are entrained by adaptations to fasting, food intake, and the postprandial state. By developing algorithms for lipid structure enrichment analysis and lipid molecular crosstalk between tissues, we find that the hepatic phosphatidylethanolamine (PE) methylation pathway is diurnally regulated, giving rise to two pools of oscillating phosphatidylcholine (PC) molecules in the circulation, which are coupled to secretion of either very low-density lipoprotein (VLDL) or high-density lipoprotein (HDL) particles. Our work demonstrates that lipid molecular timeline profiling across tissues is key to disentangling complex metabolic processes and provides a critical resource for the study of whole-body lipid metabolism.
We thank Alba Diz-Muñoz, Sabbi Lall, Nils Hoffmann, and Robert Ahrends for constructive comments and Peter Højrup for amino acid analysis. This research was supported by the VILLUM Foundation ( VKR023439 to C.S.E.), the VILLUM Center for Bioanalytical Sciences ( VKR023179 to O.N.J. and C.S.E.), and the Lundbeckfonden ( R44-A4342 and R54-A5858 to C.S.E.). The research leading to these results has received funding from the European Union Seventh Framework Programme ( FP7-2007-2013 ) under grant agreement “HEALTH-F2-2013-602222 (Athero-Flux)” (O.N.J. and C.S.E.).
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