Circadian rhythms govern metabolism, energy balance and most physiological processes, and are regulated by a 24-hour transcriptional loop that involves transcription factors Bmal1/Clock and the negative regulators Per/Cry. However, little is known about the upstream effectors that tune the circadian molecular machinery. We performed a systematic analysis and discovered that the p38 MAPK family is regulated at the transcriptional and phosphorylation level in a circadian manner. Mapk13/p38δ presented the highest amplitude and an earlier activation peak during daytime (ZT6). Mice with hepatic p38δ loss (Alb-p38δ) display reduced Bmal1 nuclear translocation and transcriptional activity. We identified Bmal1-Thr533 as a novel p38δ phosphorylation site that is crucial for its shuttling from the cytosol to the nucleus. Indirect calorimetry revealed that Alb-p38δ mice present a delayed acrophase across different metabolic (energy intake and expenditure, RER) and locomotor (rearing) parameters. RNA-seq analyses (DryR) showed that p38δ deficiency remodels the liver circadian transcriptome and elicits circadian behaviour of genes involved in fatty acid degradation, among others. Alb-p38δ mice present enhanced metabolic plasticity, driven by improved glucose uptake and disposal, and enhanced liver fatty acid oxidation. Additionally, retrained liver clock in Alb-p38δ mice protects mice from jet lag-induced insulin resistance and steatosis. Finally, human exome-phenome datamining (UKBioBank-GeneBass) revealed that MAPK13 rare variants that render p38δ constitutively active or kinase-dead are associated with insomnia or increased sleep duration, respectively.

Our data identifies p38δ as a novel upstream modulator of the circadian machinery through the phosphorylation of Bmal1, and its inactivation in the liver retrains whole-body circadian physiology. Chronotherapy and p38δ-targeted medicinal chemistry warrant further exploration in the context of liver disease and metabolic syndrome.