Updated on 2022/07/02

写真a

 
SASAKI, Hiroyuki
 
Affiliation
Faculty of Science and Engineering, Graduate School of Advanced Science and Engineering
Job title
Assistant Professor(non-tenure-track)

Degree

  • 2020.09   早稲田大学   博士(理学)

 

Research Areas

  • Sports sciences   時間運動学

Research Interests

  • 腸内細菌

  • 時間運動学

  • 時間栄養学

  • 時間生物学

  • 生理学

  • 薬理学

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Papers

  • Association Between Na, K, and Lipid Intake in Each Meal and Blood Pressure.

    Momoko Imamura, Hiroyuki Sasaki, Takae Shinto, Yu Tahara, Saneyuki Makino, Mai Kuwahara, Ayako Tada, Nanako Abe, Mikiko Michie, Shigenobu Shibata

    Frontiers in nutrition   9   853118 - 853118  2022  [International journal]

     View Summary

    Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide, and one of the most significant risk factors for CVDs is high blood pressure. Blood pressure is associated with various nutrients, such as sodium, potassium, and cholesterol. However, research focusing on the timing of intake of these nutrients and blood pressure has not been conducted. In this study, we used dietary data and a questionnaire asking about the sleep, physical activity, and blood pressure, collected from the food-log app "Asken" (total N = 2,402), to investigate the relationship between the dietary data of nutrient intake in the breakfast, lunch, and dinner and blood pressure. Daily total intake of various nutrients such as sodium, sodium-to-potassium ratio, total energy, lipid, carbohydrate, and saturated fat showed a significant association with blood pressure depending on the meal timing. From multiple regression analysis, eliminating the confounding factors, lunch sodium-to-potassium ratio, dinner energy, lipid, cholesterol, saturated fat, and alcohol intake were positively associated with blood pressure, whereas breakfast protein and lunch fiber intake showed a negative association with blood pressure. Our results suggest that nutrient intake timing is also an important factor in the prevention of high blood pressure. Our study provides possibilities to prevent hypertension by changing the timing of nutrient intake, especially sodium, together with potassium and lipids. However, because our research was limited to food-log app users, broader research regarding the general population needs to be conducted.

    DOI PubMed

  • The Combined Effects of Magnesium Oxide and Inulin on Intestinal Microbiota and Cecal Short-Chain Fatty Acids.

    Kanako Omori, Hiroki Miyakawa, Aya Watanabe, Yuki Nakayama, Yijin Lyu, Natsumi Ichikawa, Hiroyuki Sasaki, Shigenobu Shibata

    Nutrients   13 ( 1 )  2021.01  [International journal]

     View Summary

    Constipation is a common condition that occurs in many people worldwide. While magnesium oxide (MgO) is often used as the first-line drug for chronic constipation in Japan, dietary fiber intake is also recommended. Dietary fiber is fermented by microbiota to produce short-chain fatty acids (SCFAs). SCFAs are involved in regulating systemic physiological functions and circadian rhythm. We examined the effect of combining MgO and the water-soluble dietary fiber, inulin, on cecal SCFA concentration and microbiota in mice. We also examined the MgO administration timing effect on cecal SCFAs. The cecal SCFA concentrations were measured by gas chromatography, and the microbiota was determined using next-generation sequencing. Inulin intake decreased cecal pH and increased cecal SCFA concentrations while combining MgO increased the cecal pH lowered by inulin and decreased the cecal SCFA concentrations elevated by inulin. When inulin and MgO were combined, significant changes in the microbiota composition were observed compared with inulin alone. The MgO effect on the cecal acetic acid concentration was less when administered at ZT12 than at ZT0. In conclusion, this study suggests that MgO affects cecal SCFA and microbiota during inulin feeding, and the effect on acetic acid concentration is time-dependent.

    DOI PubMed

  • Ingestion of Helianthus tuberosus at Breakfast Rather Than at Dinner Is More Effective for Suppressing Glucose Levels and Improving the Intestinal Microbiota in Older Adults.

    Hyeon-Ki Kim, Hanako Chijiki, Takuya Nanba, Mamiho Ozaki, Hiroyuki Sasaki, Masaki Takahashi, Shigenobu Shibata

    Nutrients   12 ( 10 )  2020.10  [International journal]

     View Summary

    To date, nutritional studies have focused on the total intake of dietary fiber rather than intake timing. In this study, we examined the effect of the timing of daily Helianthustuberosus ingestion on postprandial and 24 h glucose levels, as well as on intestinal microbiota in older adults. In total, 37 healthy older adults (age = 74.9 ± 0.8 years) were recruited. The participants were randomly assigned to either a morning group (MG, n = 18) or an evening group (EG, n = 17). The MG and EG groups were instructed to take Helianthustuberosus powder (5 g/day) just before breakfast or dinner, respectively, for 1 week after the 1-week control period. The glucose levels of all participants were monitored using a continuous glucose monitoring system throughout the 2 weeks. The intestinal microbiota was analyzed by sequencing 16S rRNA genes from feces before and after the intervention. There were no significant differences in the physical characteristics or energy intake between groups. Helianthustuberosus intake led to decreases in tissue glucose levels throughout the day in both groups (p < 0.01, respectively). As a result of examining the fluctuations in tissue glucose levels up to 4 hours after each meal, significant decreases in the areas under the curves (AUCs) were observed for all three meals after intervention, but only in the MG (breakfast: p = 0.012, lunch: p = 0.002, dinner: p = 0.005). On the other hand, in the EG, there was a strong decrease in the AUC after dinner, but only slight decreases after breakfast and lunch (breakfast: p = 0.017, lunch: p = 0.427, dinner: p = 0.002). Moreover, the rate of change in the peak tissue glucose level at breakfast was significantly decreased in the MG compared to the EG (p = 0.027). A greater decrease was observed in the change in the blood glucose level after the ingestion of Helianthustuberosus in the MG than in the EG. Furthermore, the relative abundance of Ruminococcus in the MG at the genus level was significantly higher at baseline than in the EG (p = 0.016) and it was also significantly lower after the intervention (p = 0.013). Our findings indicate that Helianthustuberosus intake in the morning might have relatively stronger effects on the intestinal microbiota and suppress postprandial glucose levels to a greater extent than when taken in the evening.

    DOI PubMed

  • Gamma oryzanol impairs alcohol-induced anxiety-like behavior in mice via upregulation of central monoamines associated with Bdnf and Il-1β signaling.

    Salina Akter, Kazi Rasel Uddin, Hiroyuki Sasaki, Yijin Lyu, Shigenobu Shibata

    Scientific reports   10 ( 1 ) 10677 - 10677  2020.06  [International journal]

     View Summary

    Adolescent alcohol exposure may increase anxiety-like behaviors by altering central monoaminergic functions and other important neuronal pathways. The present study was designed to investigate the anxiolytic effect of 0.5% γ-oryzanol (GORZ) and its neurochemical and molecular mechanisms under chronic 10% ethanol consumption. Five-week-old ICR male mice received either control (14% casein, AIN 93 M) or GORZ (14% casein, AIN 93 M + 0.5% GORZ) diets in this study. We showed that GORZ could potentially attenuate alcohol-induced anxiety-like behaviors by significantly improving the main behavioral parameters measured by the elevated plus maze test. Moreover, GORZ treatment significantly restored the alcohol-induced downregulation of 5-hydroxytryptophan and 5-hydroxyindole acetic acid in the hippocampus and improved homovanillic acid levels in the cerebral cortex. Furthermore, a recovery increase in the level of 3-methoxy-4-hydroxyphenylglycol both in the hippocampus and cerebral cortex supported the anxiolytic effect of GORZ. The significant elevation and reduction in the hippocampus of relative mRNA levels of brain-derived neurotrophic factor and interleukin 1β, respectively, also showed the neuroprotective role of GORZ in ethanol-induced anxiety. Altogether, these results suggest that 0.5% GORZ is a promising neuroprotective drug candidate with potential anxiolytic, neurogenic, and anti-neuroinflammatory properties for treating adolescent alcohol exposure.

    DOI PubMed

  • Combinatorial Effects of Soluble, Insoluble, and Organic Extracts from Jerusalem Artichokes on Gut Microbiota in Mice.

    Hiroyuki Sasaki, Yijin Lyu, Yuki Nakayama, Fumiaki Nakamura, Aya Watanabe, Hiroki Miyakawa, Yoichi Nakao, Shigenobu Shibata

    Microorganisms   8 ( 6 )  2020.06  [International journal]

     View Summary

    Jerusalem artichokes contain high amounts of inulin, which is a prebiotic that supports digestive health, as well as a variety of insoluble fibers and caffeoylquinic acid. The individual impact of these components on gut microbiota is well known; however, the combinatorial effects are less clear. In this investigation, we fractionated Jerusalem artichokes into three parts (water-soluble extract, insoluble extract, and organic extract) and powdered them. Mice were fed a high-fat diet that included one or more of these extracts for 10 days, and then their cecal pH, cecal short-chain fatty acids (SCFAs), and fecal microbiota were evaluated. The combination of the water-soluble and organic extract decreased cecal pH and increased the concentration of SCFAs and led to dynamic changes in the composition of the gut microbiota. These results demonstrate that both the water-soluble and organic extracts in Jerusalem artichokes are bioactive substances that are capable of changing SCFA production and the composition of gut microbiota. Powdered Jerusalem artichokes, rather than inulin supplements, may be superior for promoting a healthy gut.

    DOI PubMed

  • The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy.

    Hiroaki Motohashi, Yu Tahara, Daniel S Whittaker, Huei-Bin Wang, Takahiro Yamaji, Hiromichi Wakui, Atsushi Haraguchi, Mayu Yamazaki, Hiroki Miyakawa, Koki Hama, Hiroyuki Sasaki, Tomoko Sakai, Rina Hirooka, Kengo Takahashi, Miku Takizawa, Saneyuki Makino, Shinya Aoyama, Christopher S Colwell, Shigenobu Shibata

    Kidney international   97 ( 4 ) 728 - 740  2020.04  [International journal]

     View Summary

    Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.

    DOI PubMed

  • Effects of Timing of Acute and Consecutive Catechin Ingestion on Postprandial Glucose Metabolism in Mice and Humans.

    Masaki Takahashi, Mamiho Ozaki, Miku Tsubosaka, Hyeon-Ki Kim, Hiroyuki Sasaki, Yuji Matsui, Masanobu Hibi, Noriko Osaki, Masashi Miyashita, Shigenobu Shibata

    Nutrients   12 ( 2 )  2020.02  [International journal]

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    We examined the effects of the timing of acute and consecutive epigallocatechin gallate (EGCG) and catechin-rich green tea ingestion on postprandial glucose in mice and human adults. In mouse experiments, we compared the effects of EGCG administration early (morning) and late (evening) in the active period on postprandial glucose. In human experiments, participants were randomly assigned to the morning-placebo (MP, n = 10), morning-green tea (MGT, n = 10), evening-placebo (EP, n = 9), and evening-green tea (EGT, n = 9) groups, and consumed either catechin-rich green tea or a placebo beverage for 1 week. At baseline and after 1 week, participants consumed their designated beverages with breakfast (MP and MGT) or supper (EP and EGT). Venous blood samples were collected in the fasted state and 30, 60, 120, and 180 min after each meal. Consecutive administration of EGCG in the evening, but not in the morning, reduced postprandial glucose at 30 (p = 0.006) and 60 (p = 0.037) min in the evening trials in mice. In humans, ingestion of catechin-rich green tea in the evening decreased postprandial glucose (three-factor analysis of variance, p < 0.05). Thus, catechin intake in the evening more effectively suppressed elevation of postprandial glucose.

    DOI PubMed

  • Effect of Dose and Timing of Burdock (Arctium lappa) Root Intake on Intestinal Microbiota of Mice.

    Aya Watanabe, Hiroyuki Sasaki, Hiroki Miyakawa, Yuki Nakayama, Yijin Lyu, Shigenobu Shibata

    Microorganisms   8 ( 2 )  2020.02  [International journal]

     View Summary

    Water-soluble dietary fiber such as inulin improves the beta diversity of the intestinal microbiota of mice fed with a high-fat diet (HFD). The circadian clock is the system that regulates the internal daily rhythm, and it affects the pattern of beta diversity in mouse intestinal microbiota. Burdock (Arctium lappa) root contains a high concentration of inulin/fructan (approximately 50%) and is a very popular vegetable in Japan. Arctium lappa also contains functional substances that may affect intestinal microbiota, such as polyphenols. We compared the effects of inulin and A. lappa powder on the diversity of the intestinal microbiota of HFD-fed mice. 16S rDNA from the intestinal microbiota obtained from feces was analyzed by 16S Metagenomic Sequencing Library Preparation. It was found to have a stronger effect on microbiota than inulin alone, suggesting that inulin has an additive and/or synergic action with other molecules in A. lappa root. We examined the effects of intake timing (breakfast or dinner) of A. lappa on intestinal microbiota. The intake of A. lappa root in the evening had a stronger effect on microbiota diversity in comparison to morning intake. Therefore, it is suggested that habitual consumption of A. lappa root in the evening may aid the maintenance of healthy intestinal microbiota.

    DOI PubMed

  • Gamma Oryzanol Alleviates High-Fat Diet-Induced Anxiety-Like Behaviors Through Downregulation of Dopamine and Inflammation in the Amygdala of Mice.

    Salina Akter, Kazi Rasel Uddin, Hiroyuki Sasaki, Shigenobu Shibata

    Frontiers in pharmacology   11   330 - 330  2020  [International journal]

     View Summary

    Background: A high-fat diet (HFD) can induce obesity and metabolic disorders that are closely associated with cognitive impairments, and the progression of several psychiatric disorders such as anxiety. We have previously demonstrated the anxiolytic-like effect of Gamma oryzanol (GORZ) in chronic restraint stressed mice. Objective: We studied the neurochemical and molecular mechanisms that underlie the preventive effect of GORZ in HFD-induced anxiety-like behaviors, monoaminergic dysfunction, and inflammation. Methods: Eight-week-old Institute of Cancer (ICR) male mice weighing 33-34 g were divided into the following groups and free-fed for 8 weeks: control (14% casein, AIN 93M); HFD; HFD + GORZ (0.5% GORZ). Body weight gain was checked weekly. The anxiolytic-like effects of GORZ were examined via open-field test (OFT) and elevated plus maze (EPM) test. Brain levels of monoamines [5-hydroxy tryptamine (5-HT), dopamine (DA), and norepinephrine (NE)] and their metabolites [5-hydroxyindole acetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], proinflammatory cytokines such as tumor necrosis factor-αα (Tnf-α) mRNA levels, and interleukin 1-β (Il-1β) mRNA levels in the cerebral cortex and amygdala were examined using high-performance liquid chromatography-electrochemical detection (HPLC-ECD), and real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. Results: Mice fed a HFD for eight weeks showed anxiety-like behaviors in association with HFD-induced body weight gain. GORZ potentially blocked HFD-induced anxiety-like behaviors via significant improvement of the primary behavioral parameters in behavioral tests, with a minor reduction in HFD-induced body weight gain. Furthermore, GORZ treatment significantly downregulated HFD-induced upregulation of dopamine levels in the brain's amygdala. Significant reduction of the relative mRNA expression of Tnf-α and Il-1 β was also observed in the amygdala of HFD + GORZ mice, compared to HFD mice. Conclusions: Our findings strongly suggest that 0.5% GORZ exerts anxiolytic-like effects, possibly through downregulation of dopamine, and via expression of proinflammatory cytokines Tnf-α and Il-1 β in the case of chronic HFD exposure.

    DOI PubMed

  • The Timing Effects of Soy Protein Intake on Mice Gut Microbiota.

    Konomi Tamura, Hiroyuki Sasaki, Kazuto Shiga, Hiroki Miyakawa, Shigenobu Shibata

    Nutrients   12 ( 1 )  2019.12  [International journal]

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    Soy protein intake is known to cause microbiota changes. While there are some reports about the effect of soy protein intake on gut microbiota and lipid metabolism, effective timing of soy protein intake has not been investigated. In this study, we examined the effect of soy protein intake timing on microbiota. Mice were fed twice a day, in the morning and evening, to compare the effect of soy protein intake in the morning with that in the evening. Mice were divided into three groups: mice fed only casein protein, mice fed soy protein in the morning, and mice fed soy protein in the evening under high-fat diet conditions. They were kept under the experimental condition for two weeks and were sacrificed afterward. We measured cecal pH and collected cecal contents and feces. Short-chain fatty acids (SCFAs) from cecal contents were measured by gas chromatography. The microbiota was analyzed by sequencing 16S rRNA genes from feces. Soy protein intake whether in the morning or evening led to a greater microbiota diversity and a decrease in cecal pH resulting from SCFA production compared to casein intake. In addition, these effects were relatively stronger by morning soy protein intake. Therefore, soy protein intake in the morning may have relatively stronger effects on microbiota than that in the evening.

    DOI PubMed

  • Mice Microbiota Composition Changes by Inulin Feeding with a Long Fasting Period under a Two-Meals-Per-Day Schedule.

    Hiroyuki Sasaki, Hiroki Miyakawa, Aya Watanabe, Yuki Nakayama, Yijin Lyu, Koki Hama, Shigenobu Shibata

    Nutrients   11 ( 11 )  2019.11  [International journal]

     View Summary

    Water-soluble dietary fiber is known to modulate fecal microbiota. Although there are a few reports investigating the effects of fiber intake timing on metabolism, there are none on the effect of intake timing on microbiota. Therefore, in this study, we examined the timing effects of inulin-containing food on fecal microbiota. Mice were housed under conditions with a two-meals-per-day schedule, with a long fasting period in the morning and a short fasting period in the evening. Then, 10-14 days after inulin intake, cecal content and feces were collected, and cecal pH and short-chain fatty acids (SCFAs) were measured. The microbiome was determined using 16S rDNA sequencing. Inulin feeding in the morning rather than the evening decreased the cecal pH, increased SCFAs, and changed the microbiome composition. These data suggest that inulin is more easily digested by fecal microbiota during the active period than the inactive period. Furthermore, to confirm the effect of fasting length, mice were housed under a one-meal-per-day schedule. When the duration of fasting was equal, the difference between morning and evening nearly disappeared. Thus, our study demonstrates that consuming inulin at breakfast, which is generally after a longer fasting period, has a greater effect on the microbiota.

    DOI PubMed

  • Refined Auditory Brainstem Response Measurement Identified Potential Models of Congenital Deafness in Laboratory Mouse Strains.

    Akiko Furutani, Youji Asama, Hiroyuki Sasaki, Shigenobu Shibata

    JMA journal   2 ( 2 ) 139 - 147  2019.09  [Domestic journal]

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    Introduction: To detect congenital hearing loss in mice, an objective measure is needed other than mouse behavioral observation. This study aimed to refine the methodology of auditory brainstem response measurement and identify potential congenital hearing loss models in laboratory mouse strains. Methods: Mice were anesthetized and fitted with head electrodes. Each mouse underwent four ABR measurements according to four testing conditions: A - no chamber; conventional tone; B - chamber; conventional tone; C - no chamber; short tone; D - chamber; short tone. Potential congenital hearing loss models were identified using 10 mice from each strain (C57BL, BALB/c, CH3, ICR, and ddY) through sound-attenuated ABR measurements with short-tone bursts. Potential congenital hearing loss models exhibited hearing thresholds ≥30 dB in both ears. Data were analyzed for normal distribution and variance homogeneity using the D'Agostino-Pearson/Kolmogorov-Smirnov and F value tests, respectively. One-way analysis of variance (ANOVA), with the Tukey-Kramer test, was used to conduct parametric analysis, and the Kruskal-Wallis/Friedman test, with a Dunn's test for post hoc analysis, was used to perform non-parametric analysis. Results: The simultaneous use of a sound-attenuating chamber and short-tone bursts provided clearly defined wave patterns, even at lower sound intensities. Inbred strains, especially C57BL/6 sub-strains, constitute suitable congenital hearing loss models. Conclusions: Our study shows that environmental factors should be addressed in animal studies of hearing function. Potential congenital hearing loss models may be found amongst commercially available inbred strains.

    DOI PubMed

  • Phase resetting of circadian peripheral clocks using human and rodent diets in mouse models of type 2 diabetes and chronic kidney disease.

    Shinnosuke Yasuda, Shiho Iwami, Konomi Tamura, Yuko Ikeda, Mayo Kamagata, Hiroyuki Sasaki, Atsushi Haraguchi, Masako Miyamatsu, Shizuka Hanashi, Yoshiyuki Takato, Shigenobu Shibata

    Chronobiology international   36 ( 6 ) 851 - 869  2019.06  [International journal]

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    The expression rhythms of clock genes, such as Per1, Per2, Bmal1, and Rev-erb α, in mouse peripheral clocks, are entrained by a scheduled feeding paradigm. In terms of food composition, a carbohydrate-containing diet is reported to cause strong entrainment through insulin secretion. However, it is unknown whether human diets entrain peripheral circadian clocks. In this study, we used freeze-dried diets for type 2 diabetes (DB) and chronic kidney disease (CKD), as well as low-carbohydrate diets. After 24 h of fasting, PER2::LUC knock-in mice were given access to food for 2 days during inactive periods, and bioluminescence rhythm was then measured using an in vivo imaging system. AIN-93M, the control mouse diet with a protein:fat:carbohydrate (PFC) ratio of 14.7:9.5:75.8, caused a significant phase advance (7.3 h) in the liver clock compared with that in 24 h fasted mice, whereas human diets caused significant but smaller phase advances (4.7-6.2 h). Compared with healthy and high fat/sucrose-induced DB mice, adenine-induced CKD mice showed attenuation of a phase-advance with a normal diet. There were no significant differences in phase-advance values between human diets (normal, DB, and CKD). In addition, a normal-carbohydrate diet (PFC ratio of 20.3:23.3:56.4) and a low-carbohydrate diet (PFC ratio of 36.4:42.9:20.7) caused similar phase advances in peripheral clocks. The present results strongly suggest that scheduled feeding with human diets can cause phase advances in the peripheral clocks of not only healthy, but also DB and CKD mice. This discovery provides support to the food-induced entrainment of peripheral clocks in human clinical trials.

    DOI PubMed

  • Anxiolytic effects of γ-oryzanol in chronically- stressed mice are related to monoamine levels in the brain.

    Salina Akter, Hiroyuki Sasaki, Kazi Rasel Uddin, Yuko Ikeda, Hiroki Miyakawa, Shigenobu Shibata

    Life sciences   216   119 - 128  2019.01  [International journal]

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    AIMS: The present study was aimed to investigate the anxiolytic effect of γ-oryzanol (GORZ) during chronic restraint stress treatment (CRST), which is a well-documented model of stress-related disorders, like anxiety, and its potential molecular mechanisms. MATERIALS AND METHODS: In this experiment, 5-week-old male ICR mice were used and the concentration of GORZ was fixed at 0.5% in the mouse standard diet (14% casein, AIN 93 M). Mice were immobilized daily for 3 h from ZT 2.5 to 5.5 (ZT0 was designated as light-on time) for 20 consecutive days, followed by behavioral testing, including the open field test (OFT) and elevated plus maze (EPM) test. The concentration of serum corticosterone (CORT) was measured. In addition, the expression of central monoamine neurotransmitters with their metabolites in the hippocampus, cerebral cortex, and amygdala of the brain were examined. KEY FINDINGS: 0.5% GORZ partially blocked stress-induced reduction of body weight gain while stressed mice had significantly lower body weights during the entire experimental period. Further, 0.5% GORZ treatment could significantly improve the main behavioral parameters even in CRST situations. The significant increase in serum CORT levels indicated CRST-induced stress, which was almost unaffected by 0.5% GORZ treatment. Moreover, 0.5% GORZ also supported the anxiolytic mechanism with enhancement of 5-HIAA and NE levels in the amygdala of brain after CRST. SIGNIFICANCE: Taken together, our studies suggested that 0.5% GORZ is a potential therapeutic drug candidate against anxiety under chronic stress conditions.

    DOI PubMed

  • Effects of Meal Timing on Postprandial Glucose Metabolism and Blood Metabolites in Healthy Adults.

    Masaki Takahashi, Mamiho Ozaki, Moon-Il Kang, Hiroyuki Sasaki, Mayuko Fukazawa, Tamao Iwakami, Pei Jean Lim, Hyeon-Ki Kim, Shinya Aoyama, Shigenobu Shibata

    Nutrients   10 ( 11 )  2018.11  [International journal]

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    We examined the effects of meal timing on postprandial glucose metabolism, including the incretin response and metabolites in healthy adults. Nineteen healthy young men completed two trials involving blood collection in a fasting state and at 30, 60 and 120 min after meal provision in a random order: (1) morning (~0900 h) and (2) evening (~1700 h). The blood metabolome of eight participants was analyzed using capillary electrophoresis-mass spectrometry. Postprandial glucose concentrations at 120 min (p = 0.030) and glucose-dependent insulinotropic polypeptide concentrations (p = 0.005) at 60 min in the evening trials were higher than those in the morning trials. The incremental area under the curve values of five glycolysis, tricarboxylic acid cycle and nucleotide-related metabolites and 18 amino acid-related metabolites were higher in the morning trials than those in the evening trials (p < 0.05). Partial least-squares analysis revealed that the total metabolic change was higher in the morning. Our study demonstrates that a meal in the evening exacerbates the state of postprandial hyperglycemia in healthy adults. In addition, this study provides insight into the difference of incretion and blood metabolites between breakfast and dinner, indicating that the total metabolic responses tends to be higher in the morning.

    DOI PubMed

  • γ-oryzanol ameliorates the acute stress induced by behavioral anxiety testing in mice.

    Salina Akter, Hiroyuki Sasaki, Yuko Ikeda, Hiroki Miyakawa, Shigenobu Shibata

    Journal of pharmacological sciences   138 ( 2 ) 155 - 159  2018.10  [Domestic journal]

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    We evaluated the anxiolytic effect of γ-oryzanol (GORZ) and elucidated the molecular mechanisms involved in its inhibition of behavioral test-induced anxiety. Behavioral tests were conducted on day 13, and mice were subjected to 30 min of acute restraint stress treatment (ARST) before sacrifice on day 16. In other group, behavioral tests were conducted on day 13 and 14 after ARST. 0.5% GORZ significantly weakened the effect of behavioral stress, but not the effect of strong ARST. GORZ downregulated ARST-induced cFos levels in the cerebral cortex. In conclusion, GORZ has potential ant-anxiety effect in the treatment of weak behavioral test-induced stress.

    DOI PubMed

  • Glucagon and/or IGF-1 Production Regulates Resetting of the Liver Circadian Clock in Response to a Protein or Amino Acid-only Diet.

    Yuko Ikeda, Mayo Kamagata, Mizuho Hirao, Shinnosuke Yasuda, Shiho Iwami, Hiroyuki Sasaki, Miku Tsubosaka, Yuta Hattori, Ai Todoh, Konomi Tamura, Kazuto Shiga, Teiji Ohtsu, Shigenobu Shibata

    EBioMedicine   28   210 - 224  2018.02  [International journal]

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    The circadian system controls the behavior and multiple physiological functions. In mammals, the suprachiasmatic nucleus (SCN) acts as the master pacemaker and regulates the circadian clocks of peripheral tissues. The SCN receives information regarding the light-dark cycle and is thus synchronized to the external 24-hour environment. In contrast, peripheral clocks, such as the liver clock, receive information from the SCN and other factors; in particular, food intake which leads to insulin secretion induces strong entrainment of the liver clock. On the other hand, the liver clock of insulin-depleted mice treated with streptozotocin (STZ) has been shown to be entrained by scheduled feeding, suggesting that insulin is not necessary for entrainment of the liver clock by feeding. In this study, we aimed to elucidate additional mechanism on entraining liver clock by feeding a protein-only diet and/or amino-acid administration which does not increase insulin levels. We demonstrated that protein-only diet and cysteine administration elicit entrainment of the liver clock via glucagon secretion and/or insulin-like growth factors (IGF-1) production. Our findings suggest that glucagon and/or IGF-1 production are additional key factors in food-induced entrainment.

    DOI PubMed

  • Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue.

    Yu Tahara, Mayu Yamazaki, Haruna Sukigara, Hiroaki Motohashi, Hiroyuki Sasaki, Hiroki Miyakawa, Atsushi Haraguchi, Yuko Ikeda, Shinji Fukuda, Shigenobu Shibata

    Scientific reports   8 ( 1 ) 1395 - 1395  2018.01  [International journal]

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    Microbiota-derived short-chain fatty acids (SCFAs) and organic acids produced by the fermentation of non-digestible fibre can communicate from the microbiome to host tissues and modulate homeostasis in mammals. The microbiome has circadian rhythmicity and helps the host circadian clock function. We investigated the effect of SCFA or fibre-containing diets on circadian clock phase adjustment in mouse peripheral tissues (liver, kidney, and submandibular gland). Initially, caecal SCFA concentrations, particularly acetate and butyrate, induced significant day-night differences at high concentrations during the active period, which were correlated with lower caecal pH. By monitoring luciferase activity correlated with the clock gene Period2 in vivo, we found that oral administration of mixed SCFA (acetate, butyrate, and propionate) and an organic acid (lactate), or single administration of each SCFA or lactate for three days, caused phase changes in the peripheral clocks with stimulation timing dependency. However, this effect was not detected in cultured fibroblasts or cultured liver slices with SCFA applied to the culture medium, suggesting SCFA-induced indirect modulation of circadian clocks in vivo. Finally, cellobiose-containing diets facilitated SCFA production and refeeding-induced peripheral clock entrainment. SCFA oral gavage and prebiotic supplementation can facilitate peripheral clock adjustment, suggesting prebiotics as novel therapeutic candidates for misalignment.

    DOI PubMed

  • Circadian clock-dependent increase in salivary IgA secretion modulated by sympathetic receptor activation in mice.

    Misaki Wada, Kanami Orihara, Mayo Kamagata, Koki Hama, Hiroyuki Sasaki, Atsushi Haraguchi, Hiroki Miyakawa, Atsuhito Nakao, Shigenobu Shibata

    Scientific reports   7 ( 1 ) 8802 - 8802  2017.08  [International journal]

     View Summary

    The salivary gland is rhythmically controlled by sympathetic nerve activation from the suprachiasmatic nucleus (SCN), which functions as the main oscillator of circadian rhythms. In humans, salivary IgA concentrations reflect circadian rhythmicity, which peak during sleep. However, the mechanisms controlling this rhythmicity are not well understood. Therefore, we examined whether the timing of parasympathetic (pilocarpine) or sympathetic (norepinephrine; NE) activation affects IgA secretion in the saliva. The concentrations of saliva IgA modulated by pilocarpine activation or by a combination of pilocarpine and NE activation were the highest in the middle of the light period, independent of saliva flow rate. The circadian rhythm of IgA secretion was weakened by an SCN lesion and Clock gene mutation, suggesting the importance of the SCN and Clock gene on this rhythm. Adrenoceptor antagonists blocked both NE- and pilocarpine-induced basal secretion of IgA. Dimeric IgA binds to the polymeric immunoglobulin receptor (pIgR) on the basolateral surface of epithelial cells and forms the IgA-pIgR complex. The circadian rhythm of Pigr abundance peaked during the light period, suggesting pIgR expression upon rhythmic secretion of IgA. We speculate that activation of sympathetic nerves during sleep may protect from bacterial access to the epithelial surface through enhanced secretion of IgA.

    DOI PubMed

  • Potent synchronization of peripheral circadian clocks by glucocorticoid injections in PER2::LUC-Clock/Clock mice.

    Mayo Kamagata, Yuko Ikeda, Hiroyuki Sasaki, Yuta Hattori, Shinnosuke Yasuda, Shiho Iwami, Miku Tsubosaka, Ryosuke Ishikawa, Ai Todoh, Konomi Tamura, Yu Tahara, Shigenobu Shibata

    Chronobiology international   34 ( 8 ) 1067 - 1082  2017  [International journal]

     View Summary

    In mammals, the central clock (the suprachiasmatic nuclei, SCN) is entrained mainly by the light-dark cycle, whereas peripheral clocks in the peripheral tissues are entrained/synchronized by multiple factors, including feeding patterns and endocrine hormones such as glucocorticoids. Clock-mutant mice (Clock/Clock), which have a mutation in a core clock gene, show potent phase resetting in response to light pulses compared with wild-type (WT) mice, owing to the damped and flexible oscillator in the SCN. However, the phase resetting of the peripheral clocks in Clock/Clock mice has not been elucidated. Here, we characterized the peripheral clock gene synchronization in Clock/Clock mice by daily injections of a synthetic glucocorticoid (dexamethasone, DEX) by monitoring in vivo PER2::LUCIFERASE bioluminescence. Compared with WT mice, the Clock/Clock mice showed significantly decreased bioluminescence and peripheral clock rhythms with decreased amplitudes and delayed phases. In addition, the DEX injections increased the amplitudes and advanced the phases. In order to examine the robustness of the internal oscillator, T-cycle experiments involving DEX stimulations with 24- or 30-h intervals were performed. The Clock/Clock mice synchronized to the 30-h T-cycle stimulation, which suggested that the peripheral clocks in the Clock/Clock mice had increased synchronizing ability upon DEX stimulation, to that of circadian and hour-glass type oscillations, because of weak internal clock oscillators.

    DOI PubMed

  • Age-related circadian disorganization caused by sympathetic dysfunction in peripheral clock regulation.

    Yu Tahara, Yuta Takatsu, Takuya Shiraishi, Yosuke Kikuchi, Mayu Yamazaki, Hiroaki Motohashi, Aya Muto, Hiroyuki Sasaki, Atsushi Haraguchi, Daisuke Kuriki, Takahiro J Nakamura, Shigenobu Shibata

    NPJ aging and mechanisms of disease   3   16030 - 16030  2017  [International journal]

     View Summary

    The ability of the circadian clock to adapt to environmental changes is critical for maintaining homeostasis, preventing disease, and limiting the detrimental effects of aging. To date, little is known about age-related changes in the entrainment of peripheral clocks to external cues. We therefore evaluated the ability of the peripheral clocks of the kidney, liver, and submandibular gland to be entrained by external stimuli including light, food, stress, and exercise in young versus aged mice using in vivo bioluminescence monitoring. Despite a decline in locomotor activity, peripheral clocks in aged mice exhibited normal oscillation amplitudes under light-dark, constant darkness, and simulated jet lag conditions, with some abnormal phase alterations. However, age-related impairments were observed in peripheral clock entrainment to stress and exercise stimuli. Conversely, age-related enhancements were observed in peripheral clock entrainment to food stimuli and in the display of food anticipatory behaviors. Finally, we evaluated the hypothesis that deficits in sympathetic input from the central clock located in the suprachiasmatic nucleus of the hypothalamus were in part responsible for age-related differences in the entrainment. Aged animals showed an attenuated entrainment response to noradrenergic stimulation as well as decreased adrenergic receptor mRNA expression in target peripheral organs. Taken together, the present findings indicate that age-related circadian disorganization in entrainment to light, stress, and exercise is due to sympathetic dysfunctions in peripheral organs, while meal timing produces effective entrainment of aged peripheral circadian clocks.

    DOI PubMed

  • Forced rather than voluntary exercise entrains peripheral clocks via a corticosterone/noradrenaline increase in PER2::LUC mice.

    Hiroyuki Sasaki, Yuta Hattori, Yuko Ikeda, Mayo Kamagata, Shiho Iwami, Shinnosuke Yasuda, Yu Tahara, Shigenobu Shibata

    Scientific reports   6   27607 - 27607  2016.06  [International journal]

     View Summary

    Exercise during the inactive period can entrain locomotor activity and peripheral circadian clock rhythm in mice; however, mechanisms underlying this entrainment are yet to be elucidated. Here, we showed that the bioluminescence rhythm of peripheral clocks in PER2::LUC mice was strongly entrained by forced treadmill and forced wheel-running exercise rather than by voluntary wheel-running exercise at middle time during the inactivity period. Exercise-induced entrainment was accompanied by increased levels of serum corticosterone and norepinephrine in peripheral tissues, similar to the physical stress-induced response. Adrenalectomy with norepinephrine receptor blockers completely blocked the treadmill exercise-induced entrainment. The entrainment of the peripheral clock by exercise is independent of the suprachiasmatic nucleus clock, the main oscillator in mammals. The present results suggest that the response of forced exercise, but not voluntary exercise, may be similar to that of stress, and possesses the entrainment ability of peripheral clocks through the activation of the adrenal gland and the sympathetic nervous system.

    DOI PubMed

  • Phase shifts in circadian peripheral clocks caused by exercise are dependent on the feeding schedule in PER2::LUC mice.

    Hiroyuki Sasaki, Yuta Hattori, Yuko Ikeda, Mayo Kamagata, Shiho Iwami, Shinnosuke Yasuda, Shigenobu Shibata

    Chronobiology international   33 ( 7 ) 849 - 62  2016  [International journal]

     View Summary

    Circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) clock, which is the main oscillator and peripheral clock. SCN clock can be entrained by both photic and non-photic stimuli, and an interaction exists between photic and non-photic entrainment. Moreover, peripheral circadian clocks can be entrained not only by scheduled restricted feeding, but also by scheduled exercise. Thus, the entrainment of peripheral circadian clocks may be the result of an interaction between the entrainment caused by feeding and exercise. In this study, we examined the effect of wheel-running exercise on the phase of the peripheral clocks (kidney, liver and submandibular gland) in PER2::LUC mice under various feeding schedules. Phase and waveforms of the peripheral clocks were not affected by voluntary wheel-running exercise. Exercise for a period of 4 h during the early dark period (morning) delayed the peripheral clocks, while exercise for the same duration during the late dark period (evening) advanced the peripheral clocks. The feeding phase was advanced and delayed by evening and morning exercise, respectively, suggesting that the feeding pattern elicited by the scheduled exercise may entrain the peripheral clocks. Exercise did not affect the phase of the peripheral clock under the 1 meal per day schedule. When the phase of the peripheral clocks was advanced by the feeding schedule of 2 or 4 meals per day during light and/or dark periods, wheel-running exercise during the morning period significantly and equally shifted the phase of all organs back to the original positions observed in mice maintained under free-feeding conditions and with no exercise. When the schedule of 2 meals per day during the dark period failed to affect the phase of peripheral clock, morning exercise did not affect the phase. Wheel-running exercise increased the levels of serum corticosterone, and the injection of dexamethasone/corticosterone instead of exercise shifted a phase that had advanced under the feeding schedule of 2 meals per day, back to the normal position. The liver and submandibular glands exhibit higher sensitivity to dexamethasone than the kidneys. In adrenalectomized mice, treadmill-induced normalization of the advanced phase under a feeding schedule of 2 meals per day was not observed. In summary, scheduled exercise-induced phase shifts were weaker compared to scheduled feeding-induced phase shifts. The phase advance caused by the feeding schedule of 2 or 4 meals per day was suppressed by wheel-running, treadmill exercise or dexamethasone/corticosterone injection in the early dark period (morning). Corticosterone release may be involved in exercise-induced phase shift of peripheral clocks. These results suggest that there is an interaction between the phase shifts caused by feeding and exercise schedules in peripheral clocks.

    DOI PubMed

  • Phase-delay in the light-dark cycle impairs clock gene expression and levels of serotonin, norepinephrine, and their metabolites in the mouse hippocampus and amygdala.

    Shunpei Moriya, Yu Tahara, Hiroyuki Sasaki, Jun Ishigooka, Shigenobu Shibata

    Sleep medicine   16 ( 11 ) 1352 - 1359  2015.11  [International journal]

     View Summary

    OBJECTIVE: A number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light-dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light-dark schedule would affect behavior-, circadian clock-, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice. METHODS: Mice were subjected to an 8-hour phase delay in the light-dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus. RESULTS: Locomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light-dark and inactive-active cycles. The amplitude of the day-night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light-dark-shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period. CONCLUSIONS: The present results suggest that misalignment of the internal and external clocks by continuous shifting of the light-dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice.

    DOI PubMed

  • Housing under abnormal light-dark cycles attenuates day/night expression rhythms of the clock genes Per1, Per2, and Bmal1 in the amygdala and hippocampus of mice.

    Shunpei Moriya, Yu Tahara, Hiroyuki Sasaki, Jun Ishigooka, Shigenobu Shibata

    Neuroscience research   99   16 - 21  2015.10  [International journal]

     View Summary

    Although the results of previous studies have suggested that disruptions in circadian rhythms are involved in the pathogenesis of depression, no studies have examined the interaction of clock gene expression deficit and depression state. In this study, we examined clock gene expression levels and depressive-like behavior in mice housed under 3.5h light, 3.5h dark (T = 7) conditions to investigate the association between clock gene expression and depressive state. C57BL/6J mice were housed under a T = 24 cycle (12h light, 12h dark) or a T = 7 cycle and clock gene expression levels in the hippocampus and the amygdala were measured by real-time RT-PCR. Depressive state was evaluated by the forced swim test (FST). Although circadian rhythms of Per1 and Per2 clock gene expression in the hippocampus and amygdala were still detected under T = 7 conditions, rhythmicity and expression levels of both significantly decreased. Mice housed with a T = 7 cycle showed increased immobile time in the FST than those with a T = 24 cycle. The present results suggest that the presence of a depressive state around the early active phase of activity may be related to impairment of rhythmicity and expression levels of Per1 and Per2 genes under abnormal light-dark conditions.

    DOI PubMed

  • Entrainment of the mouse circadian clock by sub-acute physical and psychological stress.

    Yu Tahara, Takuya Shiraishi, Yosuke Kikuchi, Atsushi Haraguchi, Daisuke Kuriki, Hiroyuki Sasaki, Hiroaki Motohashi, Tomoko Sakai, Shigenobu Shibata

    Scientific reports   5   11417 - 11417  2015.06  [International journal]

     View Summary

    The effects of acute stress on the peripheral circadian system are not well understood in vivo. Here, we show that sub-acute stress caused by restraint or social defeat potently altered clock gene expression in the peripheral tissues of mice. In these peripheral tissues, as well as the hippocampus and cortex, stressful stimuli induced time-of-day-dependent phase-advances or -delays in rhythmic clock gene expression patterns; however, such changes were not observed in the suprachiasmatic nucleus, i.e. the central circadian clock. Moreover, several days of stress exposure at the beginning of the light period abolished circadian oscillations and caused internal desynchronisation of peripheral clocks. Stress-induced changes in circadian rhythmicity showed habituation and disappeared with long-term exposure to repeated stress. These findings suggest that sub-acute physical/psychological stress potently entrains peripheral clocks and causes transient dysregulation of circadian clocks in vivo.

    DOI PubMed

  • Eating meals before wheel-running exercise attenuate high fat diet-driven obesity in mice under two meals per day schedule.

    Hiroyuki Sasaki, Yuta Hattori, Yuko Ikeda, Mayo Kamagata, Shigenobu Shibata

    Chronobiology international   32 ( 5 ) 677 - 86  2015.06  [International journal]

     View Summary

    Mice that exercise after meals gain less body weight and visceral fat compared to those that exercised before meals under a one meal/exercise time per day schedule. Humans generally eat two or three meals per day, and rarely have only one meal. To extend our previous observations, we examined here whether a "two meals, two exercise sessions per day" schedule was optimal in terms of maintaining a healthy body weight. In this experiment, "morning" refers to the beginning of the active phase (the "morning" for nocturnal animals). We found that 2-h feeding before 2-h exercise in the morning and evening (F-Ex/F-Ex) resulted in greater attenuation of high fat diet (HFD)-induced weight gain compared to other combinations of feeding and exercise under two daily meals and two daily exercise periods. There were no significant differences in total food intake and total wheel counts, but feeding before exercise in the morning groups (F-Ex/F-Ex and F-Ex/Ex-F) increased the morning wheel counts. These results suggest that habitual exercise after feeding in the morning and evening is more effective for preventing HFD-induced weight gain. We also determined whether there were any correlations between food intake, wheel rotation, visceral fat volume and skeletal muscle volumes. We found positive associations between gastrocnemius muscle volumes and morning wheel counts, as well as negative associations between morning food intake volumes/body weight and morning wheel counts. These results suggest that morning exercise-induced increase of muscle volume may refer to anti-obesity. Evening exercise is negatively associated with fat volume increases, suggesting that this practice may counteract fat deposition. Our multifactorial analysis revealed that morning food intake helps to increase exercise, and that evening exercise reduced fat volumes. Thus, exercise in the morning or evening is important for preventing the onset of obesity.

    DOI PubMed

  • Feeding and adrenal entrainment stimuli are both necessary for normal circadian oscillation of peripheral clocks in mice housed under different photoperiods.

    Yuko Ikeda, Hiroyuki Sasaki, Teiji Ohtsu, Takuya Shiraishi, Yu Tahara, Shigenobu Shibata

    Chronobiology international   32 ( 2 ) 195 - 210  2015.03  [International journal]

     View Summary

    The mammalian circadian rhythm is entrained by multiple factors, including the light-dark cycle, the organism's feeding pattern and endocrine hormones such as glucocorticoids. Both a central clock (the suprachiasmatic nucleus, or SCN) and peripheral clocks (i.e. in the liver and lungs) in mice are entrained by photoperiod. However, the factors underlying entrainment signals from the SCN to peripheral clocks are not well known. To elucidate the role of entrainment factors such as corticosterone and feeding, we examined whether peripheral clock rhythms were impaired by adrenalectomy (ADX) and/or feeding of 6 meals per day at equal intervals under short-day, medium-day and long-day photoperiods (SP, MP and LP, respectively). We evaluated the waveform and phase of circadian rhythms in the liver, kidney and salivary gland by in vivo imaging of PER2::LUCIFERASE knock-in mice. In intact mice, the waveforms of the peripheral clocks were similar among all photoperiods. The phases of peripheral clocks were well adjusted by the timing of the "lights-off"-operated evening (E) oscillator but not the "lights-on"-operated morning (M) oscillator. ADX had almost no effect on the rhythmicity and phase of peripheral clocks, regardless of photoperiod. To reduce the feeding-induced signal, we placed mice on a restricted feeding regimen with 6 meals per day (6 meals RF). This caused advances of the peripheral clock phase in LP-housed mice (2-5 h) and MP-housed mice (1-2 h) but not SP-housed mice. Thus, feeding pattern may affect the phase of peripheral clocks, depending on photoperiod. More specifically, ADX + 6 meals RF mice showed impairment of circadian rhythms in the kidney and liver but not in the salivary gland, regardless of photoperiod. However, the impairment of peripheral clocks observed in ADX + 6 meals RF mice was reversed by administration of dexamethasone for 3 days. The phase differences in the salivary gland clock among SP-, MP- and LP-housed mice became very small following treatment with ADX + 6 meals RF, suggesting that the effect of photoperiod was reduced by ADX and 6 meals RF. Because the SCN rhythm (as evaluated by PER2 immunohistochemistry) was not disrupted by ADX + 6 meals RF, impairment of peripheral clocks in these mice was not because of impaired SCN clock function. In addition, locomotor activity rhythm and modifications of the feeding pattern may not be completely responsible for determining the phase of peripheral clocks. Thus, this study demonstrates that the phase of peripheral clocks responds to a photoperiodic lights-off signal, and suggests that signals from normal feeding patterns and the adrenal gland are necessary to maintain the oscillation and phase of peripheral clocks under various photoperiods.

    DOI PubMed

  • Combination of meal and exercise timing with a high-fat diet influences energy expenditure and obesity in mice.

    Hiroyuki Sasaki, Teiji Ohtsu, Yuko Ikeda, Miku Tsubosaka, Shigenobu Shibata

    Chronobiology international   31 ( 9 ) 959 - 75  2014.11  [International journal]

     View Summary

    In mice, obesity has been observed not only in those freely fed a high-fat diet (HFD) but also in those fed while physically inactive. In contrast, a HFD during physically active periods protects against obesity and the impairments in the circadian rhythm induced by free feeding of a HFD. Although exercise is known to be effective for obesity prevention and management, the optimal timing of exercise has not yet been determined. In the present experiments, we aimed to determine the best combination of daily timing of HFD consumption and exercise for the prevention of HFD-induced weight gain in mice. In this experiment, "morning" refers to the beginning of the active phase (the "morning" for nocturnal animals). Increases in body weight related to free feeding of a HFD was significantly reduced with 4 h of exercise during the late (evening) or middle (noon) active period compared to 4 h of exercise during the early (morning) active period or free access to exercise, which resulted in hours of exercise similar to that of morning exercise. These results suggested that eating in the morning or at noon followed by exercise in the evening could prevent weight gain more effectively than exercise in the morning followed by eating at noon or in the evening. The group fed a HFD for 4 h in the morning had lower body weight than the group fed a HFD for 4 h in the evening without exercise. The last group of experiments tested the hypothesis that there would be an interaction between mealtime and exercise time (i.e. time of day) versus order (i.e. which comes first) effects. We compared groups that exercised for 4 h at noon and were fed either in the morning or evening and groups that were fed for 4 h at noon and either exercised in the morning or evening. We found that the groups that were fed before exercise gained less body and fat weight and more skeletal muscle weight compared to the groups that exercised before eating. Corresponding to the body and fat weight changes, the respiratory exchange ratio (RER) was lower and energy expenditure was higher in the groups fed before exercise than in the groups fed after exercise, and these effects on energy metabolism were also observed in the early stage of HFD feeding before obesity. When obese mice fed a HFD for 12 weeks were exposed to a combination of feeding and exercise timing in an effort to reduce body weight, eating followed by exercise resulted in greater weight loss, similar to the experiments conducted to prevent weight gain. These results demonstrate that a combination of daily timing of eating and exercise may influence weight gain and that eating followed by exercise may be effective for minimizing increases in body and fat weight as well as maximizing increases in skeletal muscle weight.

    DOI PubMed

  • Effect of quetiapine on Per1, Per2, and Bmal1 clock gene expression in the mouse amygdala and hippocampus.

    Shunpei Moriya, Yu Tahara, Hiroyuki Sasaki, Yutaro Hamaguchi, Daisuke Kuriki, Ryosuke Ishikawa, Jun Ishigooka, Shigenobu Shibata

    Journal of pharmacological sciences   125 ( 3 ) 329 - 32  2014  [Domestic journal]

     View Summary

    Circadian rhythms are related to various psychiatric disorders. Recently, antipsychotics, including quetiapine (QTP), have been accepted as potential therapeutic agents for the treatment of depression, but its mechanism remains poorly understood. In this study, we examined clock gene fluctuation patterns in QTP-treated mice. QTP significantly increased Per2 mRNA at ZT12 and Per1 and Per2 expression at ZT18 in the amygdala. There were significant differences between the control and QTP groups in the cross-time effects of Per2 mRNA expression in the amygdala. Our findings suggest that QTP possibly acts on the circadian system, which then induces changes in mood symptoms.

    PubMed

  • [Chrono-nutrition and chrono-exercise].

    Shigenobu Shibata, Hiroyuki Sasaki, Yuko Ikeda

    Nihon rinsho. Japanese journal of clinical medicine   71 ( 12 ) 2194 - 9  2013.12  [Domestic journal]

     View Summary

    The circadian rhythm controls many physiological functions, such as feeding, motor activity, endocrine secretion and autonomic nerve. Regular feeding pattern can entrain the peripheral circadian clock, whereas peripheral clock systems can control the absorption distribution, metabolism and excretion of nutrients, suggesting mutual interactions between circadian clocks and nutrition/food. The interactions were so-called by "chrono-nutrition", and bigger meals for breakfast were good for entrainment of peripheral clock and protection of obesity. Similar to chrono-nutrition the timing of exercise ("chrono-exercise") is important for both entrainment signals and energy expenditure. Evening exercise and/or feeding then exercise was good timing exercise for protection of obesity. Taken all, it is suggested that timing of feeding and exercise is now one of key factors for metabolic syndrome.

    PubMed

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Books and Other Publications

  • 時間栄養学 : 時計遺伝子、体内時計、食生活をつなぐ

    柴田, 重信

    化学同人  2020.06 ISBN: 9784759820362

  • 食と医療 Vor.12

    講談社エディトリアル,講談社 (発売)  2020.01

Misc

  • マウスを用いたカフェインの抗肥満効果に関する時間栄養学的研究

    山崎智弘, 原口敦嗣, 西村祐太郎, 大久保仁, 佐々木裕之, 佐々木裕之, 田村好, 志賀一登, 柴田重信

    日本栄養・食糧学会大会講演要旨集   72nd  2018

    J-GLOBAL

Specific Research

  • マウスを用いたセカンドミール効果のメカニズム探索

    2021  

     View Summary

    心血管疾患などのリスクを抑えるために、食後高血糖を予防・改善することは重要であることが知られている。食後高血糖を抑えるための食事方法として「セカンドミール効果」が提唱されている。このセカンドミール効果はヒト研究において多く報告がなされているが、マウスでの報告はほとんどなく、そのメカニズムについても詳細は不明である。そこで、本研究では、マウスを用いたセカンドミール効果が見られるモデルの作製およびメカニズムの探索を目的とした。その結果、マウスの活動期はじめにファーストミール、活動期おわりにセカンドミールを食べるスケジュールによってセカンドミール効果が見られ、モデルを作成することができた。

  • 腸内細菌叢の改善を目指した運動実施の時間運動学的研究

    2020  

     View Summary

    哺乳類の腸内には約40兆個もの細菌が生息しており、この集団を腸内細菌叢と呼ぶ。腸内細菌叢は宿主の生理状態と密接に関わっており、腸内細菌叢のバランスを整えることが健康状態の保持につながる。適度な運動は腸内細菌叢のバランスを整えることが知られているが、運動の実施タイミングついては検証されていない。本研究で、マウスを用いて、腸内細菌叢の改善に最も効果的な運動の実施タイミングを解明することを目的とし、実験を行った。その結果、朝の時間帯よりも夕の時間帯に運動をすることで、腸内細菌叢の構成を大きく変動させることが示唆された。本研究では、運動の時間帯のみに着目して実験を行ったが、今後は、運動の強度や種類についても検証を行う。

 

Syllabus

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