General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. AbstractThe mammalian circadian system consists of a master clock in the brain that synchronizes subsidiary oscillators in peripheral tissues. The master clock maintains phase coherence in peripheral cells through systemic cues such as feeding-fasting and temperature cycles. Here we examined the role of oxygen as a resetting cue for circadian clocks. We continuously measured oxygen levels in living animals and detected daily rhythms in tissue oxygenation. Oxygen cycles, within the physiological range, were sufficient to synchronize cellular clocks in HIF1α-dependent manner. Furthermore, several clock genes responded to changes in oxygen levels through HIF1α. Finally, we found that a moderate reduction in oxygen levels for a short period accelerates the adaptation of wild type but not of HIF1α-deficient mice to the new time in a jet lag protocol. We conclude that oxygen, via HIF1α activation, is a resetting cue for circadian clocks and propose oxygen modulation as therapy for jet lag.

Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.M itochondria serve as major suppliers of cellular energy through nutrient oxidation. One of the major challenges that mitochondria face is the adaptation to changes in nutrient supply and energy demand. An inability of mitochondria to deal with altered nutrient environment is associated with metabolic diseases, such as diabetes and obesity (1, 2).Mitochondria oxidize carbohydrates and lipids to generate ATP by a process known as oxidative phosphorylation. Pyruvate and fatty acids are transported from the cytoplasm into the mitochondrial matrix, where they are catabolized into acetyl CoA. Pyruvate is converted to acetyl CoA through the action of the pyruvate dehydrogenase complex (PDC), whereas fatty acids are oxidized through a cycle of reactions that trim two carbons at a time, generating one molecule of acetyl CoA in each cycle [i.e., fatty acid oxidation (FAO)]. The acetyl groups are then fed into the Krebs cycle for additional degradation, and the process culminates with the transfer of acetyl-derived high-energy electrons along the respiratory chain.Mounting evidence suggests that circadian clocks orchestrate our daily physiology and metabolism (3-6). The mammalian circadian timing system consists of a central pacemaker in the brain that is entrained by daily light-dark cycles and synchronizes subsidiary oscillators in virtually all cells of the body, in part by driving rhythmic feeding behavior. The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8-12) and more recently, several proteomics (13-15) and metabolomics studies (16-21) highlighted the pervasive circadian control of metabolism.Rest-activity and feeding-fasting cycles that naturally occur throughout the day impose pronounced changes in nutrient s...

Highlights d Mice and humans show daily variance in exercise capacity d Exercise intensity and clock proteins affect daytime variance in exercise capacity d Exercise elicits distinct daytime muscle transcriptomic and metabolic signature d ZMP, an AMPK activator, is induced by exercise in a daytimedependent manner

Daily rhythms in animal physiology are driven by endogenous circadian clocks in part through rest-activity and feeding-fasting cycles. Here, we examined principles that govern daily respiration. We monitored oxygen consumption and carbon dioxide release, as well as tissue oxygenation in freely moving animals to specifically dissect the role of circadian clocks and feeding time on daily respiration. We found that daily rhythms in oxygen and carbon dioxide are clock-controlled and that time-restricted feeding restores their rhythmicity in clock-deficient mice. Remarkably, day-time feeding dissociated oxygen rhythms from carbon dioxide oscillations, whereby oxygen followed activity and carbon dioxide was shifted and aligned with food intake. In addition, changes in carbon dioxide levels altered clock gene expression and phase-shifted the clock. Collectively, our findings indicate that oxygen and carbon dioxide rhythms are clock-controlled and feeding-regulated, and support a potential role for carbon dioxide in phase resetting of peripheral clocks upon feeding.

Ornithine aminotransferase (L-ornithine 2-oxoacid aminotransferase, OAT) is widely expressed in organs, but studies in mice have focused primarily on the intestine, kidney and liver because of the high OAT-specific activity in these tissues. This study aimed to investigate OAT activity in adult mouse tissues to assess the potential contribution to ornithine metabolism and to determine OAT control during postnatal development. OAT activity was widely distributed in mouse tissues. Sexual dimorphism was observed for most tissues in adults, with greater activity in females than in males. The contribution of skeletal muscles to total OAT activity (34% in males and 27% in females) was the greatest (50%) of the investigated tissues in pre-weaned mice and was similar to that of the liver in adults. OAT activity was found to be regulated in a tissue-specific manner during postnatal development in parallel with large changes in the plasma testosterone and corticosterone levels. After weaning, OAT activity markedly increased in the liver but dropped in the skeletal muscle and adipose tissue. Anticipating weaning for 3 days led to an earlier reduction of OAT activity in skeletal muscles. Orchidectomy in adults decreased OAT activity in the liver but increased it in skeletal muscle and adipose tissue. We concluded that the contribution of skeletal muscle to mouse ornithine metabolism may have been underestimated. The regulation of OAT in skeletal muscles differs from that in the liver. The present findings suggest important and tissue-specific metabolic roles for OAT during postnatal development in mice.