The circadian clock is closely related to human health, such as metabolic syndrome and cardiovascular disease. Our previous study revealed that irregular feeding induced abnormal lipid metabolism with disruption of the hepatic circadian clock. We hypothesized that breakfast skipping induces lipid abnormalities, such as adiposity, by altering the hepatic circadian oscillation of clock and lipid metabolism-related genes. Here, we established a delayed first active-phase meal (DFAM) protocol as a breakfast-skipping model. Briefly, rats were fed a high-fat diet during zeitgeber time (ZT) 12–24 in a control group and ZT 16–4 in the DFAM group. The DFAM group showed increased body weight gain and perirenal adipose tissue weight without a change in total food intake. The circadian oscillations of hepatic clock and de novo fatty acid synthesis genes were delayed by 2–4 h because of DFAM. The peaks of serum insulin, a synchronizer for the liver clock, bile acids, and non-esterified fatty acid (NEFA) were delayed by 4–6 h because of DFAM. Moreover, DFAM delayed the surge in body temperature by 4 h and may have contributed to the increase in body weight gain and adipose tissue weight because of decreased energy expenditure. These data indicated a potential molecular mechanism by which breakfast skipping induces abnormal lipid metabolism, which is related to the altered circadian oscillation of hepatic gene expression. The results also suggested that the delayed peaks of serum NEFA, bile acids, and insulin entrain the circadian rhythm of hepatic clock and lipid metabolism-related genes.

The etiology of metabolic syndrome involves several complicated factors. One of the main factors contributing to metabolic syndrome has been proposed to be excessive intake of sucrose, which disturbs hepatic lipid metabolism, resulting in fatty liver. However, the mechanism by which sucrose induces fatty liver remains to be elucidated. Considering feeding behavior important for metabolism, we investigated whether time-restricted feeding of high sucrose diet (HSD), only in the active phase (the dark phase of the daily light/dark cycle), would ameliorate adverse effects of sucrose on lipid homeostasis in rats. Male Wistar rats, fed either an ad libitum (ad lib.) or time-restricted control starch diet (CD) or HSD were investigated. Rats fed ad lib. (CD and HSD) completed approximately 20% of food intake in the daytime. Time-restricted feeding did not significantly suppress total food intake of rats. However, time-restricted feeding of HSD significantly suppressed the increased plasma triglyceride levels. Moreover, time-restricted feeding also ameliorated HSD-induced liver lipid accumulation, whereas circadian oscillations of liver clock gene or transcriptional factor gene expression for lipid metabolism were not altered significantly. These results demonstrated that restricting sucrose intake only during the active phase in rats ameliorates the abnormal lipid metabolism caused by excess sucrose intake.

We have shown that intake of sesame seed and its lignan increases vitamin E concentrations and decreases urinary excretion levels of vitamin E metabolites in male Wistar rats, suggesting inhibition of vitamin E catabolism by sesame lignan. The aim of this study was to examine whether dietary sesame seed also increased vitamin K concentrations, because its metabolic pathway is similar to that of vitamin E. To test the effect of sesame lignan on vitamin K concentrations, male Wistar rats were fed a control diet or a diet with 0.2% sesamin (a sesame lignan) for 7 d in experiment 1. Liver phylloquinone (PK), menaquinone-4 (MK-4), and γ-tocopherol were greater in rats fed sesamin than in control rats. To test the effect of sesame seed on vitamin K concentrations, male Wistar rats were fed a control diet or a diet with 1, 5, or 10% sesame seed for 3 d in experiment 2. Liver and kidney PK and γ-tocopherol but not MK-4 were greater in rats fed sesame seed than in control rats, although differences in dietary amounts of sesame seed did not affect the PK concentrations. For further confirmation of the effect of sesame seed, male Wistar rats were fed a control diet or a diet with 20% sesame seed for 40 d in experiment 3. Kidney, heart, lung, testis, and brain PK and brain MK-4 were greater in rats fed sesame seed than in control rats. The present study revealed for the first time, to our knowledge, that dietary sesame seed and sesame lignan increase not only vitamin E but also vitamin K concentrations in rat tissues.

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Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.

This work was supported by Japan Society for the Promotion of Science (JSPS) Grants 21658052, 25292069, and 16H04922 (to H. O.). The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1-S3 and Figs. S1 and S2. 1 Recipient of an award from the Otsuka Toshimi Scholarship Foundation.

From an enzyme kinetic study using rat liver microsomes, α-tocopherol has been suggested to accelerate the other vitamin E catabolism by stimulating vitamin E ω-hydroxylation, the late limiting reaction of the vitamin E catabolic pathway. To test the effect of α-tocopherol on catabolism of the other vitamin E isoforms in vivo, we determined whether α-tocopherol accelerates depletion of γ-tocopherol and tocotrienol and excretion of their metabolites in rats. Male Wistar rats were fed a γ-tocopherol-rich diet for 6 weeks followed by a γ-tocopherol-free diet with or without α-tocopherol for 7 days. Intake of γ-tocopherol-free diets lowered γ-tocopherol concentrations in serum, liver, adrenal gland, small intestine, and heart, but there was no effect of dietary α-tocopherol on γ-tocopherol concentrations. The level of urinary excretion of γ-tocopherol metabolite was not affected by dietary α-tocopherol. Next, the effect of α-tocopherol on tocotrienol depletion was examined using rats fed a tocotrienol-rich diet for 6 weeks. Subsequent intake of a tocotrienol-free diet with or without α-tocopherol for 7 days depleted concentrations of α- and γ-tocotrienol in serum and tissues, which was accompanied by a decrease in the excretion of γ-tocotrienol metabolite. However, neither the tocotrienol concentration nor γ-tocotrienol metabolite excretion was affected by dietary α-tocopherol. These data showed that dietary α-tocopherol did not accelerate the depletion of γ-tocopherol and tocotrienol and their metabolite excretions, suggesting that the positive effect of α-tocopherol on vitamin E ω-hydroxylase is not sufficient to affect the other isoform concentrations in tissues.

Background: To investigate whether shifted timing of eating, breakfast skipping, induces alterations in the circadian clock and abnormal lipid metabolism, we have established a delayed meal timing (DMT) protocol for rats, which started eating food 4 h delay. In the present study, control and DMT rats were fed a high-cholesterol diet during zeitgeber time (ZT) 12-24 and ZT 16-4, respectively. The DMT protocol increased the hepatic lipids and epididymal adipose tissue weight without changes in food intake and body weight. The surge in body temperature was delayed by 4 h in the DMT group, suggesting that energy expenditure was decreased in response to DMT. The peaks of the diurnal rhythm of serum non-esterified fatty acids and insulin were delayed by 2 and 4 h due to DMT, respectively. The oscillation peaks of hepatic de novo fatty acid synthesis gene expression was delayed by 4 h in response to DMT, whereas the peak of hepatic clock genes were 2 h delayed or not by DMT. Although metabolic oscillation is considered to be controlled by clock genes, the disintegration rhythms between the clock genes and lipid metabolism-related genes were not observed in rats fed a high-fat diet in our previous study. These data suggest that the circadian rhythm of de novo fatty acid metabolism is regulated by timing of eating, but is not directly controlled by clock genes. The present study suggests that breakfast skipping would complicate fatty liver and body fat accumulation.