Updated on 2022/05/19

写真a

 
HARAGUCHI, Atsushi
 
Affiliation
Faculty of Science and Engineering, School of Advanced Science and Engineering
Job title
Assistant Professor(without tenure)

Education

  • 2015.04
    -
    2018.03

    Waseda University   Graduate School of Advanced Science and Engineering  

  • 2013.04
    -
    2015.03

    Waseda University   Graduate School of Advanced Science and Engineering  

  • 2009.04
    -
    2013.03

    Waseda University   School of Advanced Science and Engineering  

Degree

  • 早稲田大学   博士(理学)

Research Experience

  • 2019.04
    -
    Now

    Waseda University   School of Advanced Science and Engineering

  • 2018.04
    -
    2019.03

    Japan Society for the Promotion of Science

  • 2017.04
    -
    2018.03

    Japan Society for the Promotion of Science

Professional Memberships

  •  
     
     

    JAPAN SOCIETY OF NUTRITION AND FOOD SCIENCE

  •  
     
     

    THE PHYSIOLOGICAL SOCIETY OF JAPAN

  •  
     
     

    JAPANESE SOCIETY FOR CHRONOBIOLOGY

  •  
     
     

    日本時間栄養学会

  •  
     
     

    Society for Research on Biological Rhythms

  •  
     
     

    European Biological Rhythms Society

  •  
     
     

    THE PHARMACEUTICAL SOCIETY OF JAPAN

▼display all

 

Research Areas

  • Nutrition science and health science

  • Food sciences

  • Animal physiological chemistry, physiology and behavioral biology

  • Physiology

Research Interests

  • 時間栄養学

  • 行動生理学

  • Physiology

  • nutirition

  • Chronobiology

Papers

  • Use of a social jetlag-mimicking mouse model to determine the effects of a two-day delayed light- and/or feeding-shift on central and peripheral clock rhythms plus cognitive functioning.

    Atsushi Haraguchi, Yutaro Nishimura, Miyabi Fukuzawa, Yosuke Kikuchi, Yu Tahara, Shigenobu Shibata

      38 ( 3 ) 426 - 442  2021.03  [Refereed]

    Authorship:Lead author

  • Crosstalk Among Circadian Rhythm, Obesity and Allergy

    Kanami Orihara, Atsushi Haraguchi, Shigenobu Shibata

    Int J Mol Sci .   21 ( 5 ) 1884  2020.03  [Refereed]  [Invited]

  • 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    2020.01  [Refereed]  [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

  • Correlation among clock gene expression rhythms, sleep quality, and meal conditions in delayed sleep-wake phase disorder and night eating syndrome.

    Haraguchi A, Komada Y, Inoue Y, Shibata S

    Chronobiology international   36 ( 6 ) 770 - 783  2019.06  [Refereed]

    Authorship:Lead author

    DOI PubMed

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

    Yasuda S, Iwami S, Tamura K, Ikeda Y, Kamagata M, Sasaki H, Haraguchi A, Miyamatsu M, Hanashi S, Takato Y, Shibata S

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

     View Summary

    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

  • A low-protein diet eliminates the circadian rhythm of serum insulin and hepatic lipid metabolism in mice.

    Yokota SI, Nakamura K, Ando M, Haraguchi A, Omori K, Shibata S

    The Journal of nutritional biochemistry   63   177 - 185  2019.01  [Refereed]

    DOI PubMed

  • Day-Night Oscillation of Atrogin1 and Timing-Dependent Preventive Effect of Weight-Bearing on Muscle Atrophy.

    Shinya Aoyama, Shuichi Kojima, Keisuke Sasaki, Ryosuke Ishikawa, Mizuho Tanaka, Takeru Shimoda, Yuta Hattori, Natsumi Aoki, Kengo Takahashi, Rina Hirooka, Miku Takizawa, Atsushi Haraguchi, Shigenobu Shibata

    EBioMedicine   37   499 - 508  2018.11  [Refereed]  [International journal]

     View Summary

    BACKGROUND: Atrogin1, which is one of the key genes for the promotion of muscle atrophy, exhibits day-night variation. However, its mechanism and the role of its day-night variation are largely unknown in a muscle atrophic context. METHODS: The mice were induced a muscle atrophy by hindlimb-unloading (HU). To examine a role of circadian clock, Wild-type (WT) and Clock mutant mice were used. To test the effects of a neuronal effects, an unilateral ablation of sciatic nerve was performed in HU mice. To test a timing-dependent effects of weight-bearing, mice were released from HU for 4 h in a day at early or late active phase (W-EAP and W-LAP groups, respectively). FINDINGS: We found that the day-night oscillation of Atrogin1 expression was not observed in Clock mutant mice or in the sciatic denervated muscle. In addition, the therapeutic effects of weight-bearing were dependent on its timing with a better effect in the early active phase. INTERPRETATION: These findings suggest that the circadian clock controls the day-night oscillation of Atrogin1 expression and the therapeutic effects of weight-bearing are dependent on its timing. FUND: Council for Science, Technology, and Innovation, SIP, "Technologies for creating next-generation agriculture, forestry, and fisheries".

    DOI PubMed

  • A randomized, double-blind and placebo-controlled crossover trial on the effect of l-ornithine ingestion on the human circadian clock.

    Fukuda T, Haraguchi A, Takahashi M, Nakaoka T, Fukazawa M, Okubo J, Ozaki M, Kanatome A, Ohya R, Miura Y, Obara K, Shibata S

    Chronobiology international   35 ( 10 ) 1 - 11  2018.07  [Refereed]

    Authorship:Lead author

    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  [Refereed]  [International journal]

     View Summary

    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

  • Night eating model shows time-specific depression-like behavior in the forced swimming test.

    Atsushi Haraguchi, Miyabi Fukuzawa, Shiho Iwami, Yutaro Nishimura, Hiroaki Motohashi, Yu Tahara, Shigenobu Shibata

    Scientific reports   8 ( 1 ) 1081 - 1081  2018.01  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    The circadian clock system is associated with feeding and mood. Patients with night eating syndrome (NES) delay their eating rhythm and their mood declines during the evening and night, manifesting as time-specific depression. Therefore, we hypothesized that the NES feeding pattern might cause time-specific depression. We established new NES model by restricted feeding with high-fat diet during the inactive period under normal-fat diet ad libitum. The FST (forced swimming test) immobility time in the NES model group was prolonged only after lights-on, corresponding to evening and early night for humans. We examined the effect of the NES feeding pattern on peripheral clocks using PER2::LUCIFERASE knock-in mice and an in vivo monitoring system. Caloric intake during the inactive period would shift the peripheral clock, and might be an important factor in causing the time-specific depression-like behavior. In the NES model group, synthesis of serotonin and norepinephrine were increased, but utilization and metabolism of these monoamines were decreased under stress. Desipramine shortened some mice's FST immobility time in the NES model group. The present study suggests that the NES feeding pattern causes phase shift of peripheral clocks and malfunction of the monoamine system, which may contribute to the development of time-specific depression.

    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  2017.08  [Refereed]

     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

  • Polyporus and Bupleuri radix effectively alter peripheral circadian clock phase acutely in male mice.

    Hiroaki Motohashi, Haruna Sukigara, Yu Tahara, Keisuke Saito, Mayu Yamazaki, Takuya Shiraishi, Yosuke Kikuchi, Atsushi Haraguchi, Shigenobu Shibata

    Nutrition research (New York, N.Y.)   43   16 - 24  2017.07  [Refereed]  [International journal]

     View Summary

    In mammals, daily physiological events are precisely regulated by an internal circadian clock system. An important function of this system is to readjust the phase of the clock daily. In Japan, traditional herb medicines, so-called crude drugs (Shoyaku), are widely used for many diseases, and some are reported to affect circadian clock impairment, suggesting that some of them might have an ability to modify clock gene expression rhythms. Therefore, from selected 40 crude drugs, finding candidates that control the circadian clock phases was the first purpose of this study. As there are several crude drugs used for liver- and/or kidney-related diseases, the second aim of the present study was to find some crude drugs affecting liver/kidney circadian clock in vivo. To assess phase changes in the daily circadian rhythm, bioluminescence from the core clock gene product Period 2 was continuously monitored in mouse embryonic fibroblasts in vitro and in some peripheral tissues (kidney, liver, and submandibular gland) of PERIOD2::LUCIFERASE knock-in mice in vivo. In our screening, Polyporus and Bupleuri radix were found to be good candidates to effectively manipulate the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. Interestingly, Polyporus and Bupleuri radix are traditional herb medicines use for treating edema and promoting diuresis, and for chronic hepatitis, respectively. These crude drugs may be therefore good modulators of the circadian peripheral clocks including liver and kidney, and circadian clock genes become new molecular targets for these crude drugs.

    DOI PubMed

  • Positive association between physical activity and PER3 expression in older adults.

    Masaki Takahashi, Atsushi Haraguchi, Yu Tahara, Natsumi Aoki, Mayuko Fukazawa, Kumpei Tanisawa, Tomoko Ito, Takashi Nakaoka, Mitsuru Higuchi, Shigenobu Shibata

    Scientific reports   7   39771 - 39771  2017.01  [Refereed]  [International journal]

     View Summary

    The circadian clock regulates many physiological functions including physical activity and feeding patterns. In addition, scheduled exercise and feeding themselves can affect the circadian clock. The purpose of the present study was to investigate the relationship between physical/feeding activity and expression of clock genes in hair follicle cells in older adults. Twenty adult men (age, 68 ± 7 years, mean ± SE) were examined in this cross-sectional study. Prior to hair follicle cell collection, the participants were asked to wear a uniaxial accelerometer for one week. The timings of breakfast, lunch, and dinner were also recorded. Hair follicle cells were then collected over a 24 h period at 4 h intervals. The amplitude of PER3 expression was positively correlated with moderate and vigorous physical activity (r = 0.582, p = 0.007) and peak oxygen uptake (r = 0.481, p = 0.032), but these correlations were not observed for NR1D1 or NR1D2. No association was noted between meal times and the amplitude or the acrophase for any of these three clock genes. These findings suggest that rhythmic expression of the circadian clock gene PER3 is associated with the amount of daily physical activity and physical fitness in older adults.

    DOI PubMed

  • Potent Effects of Flavonoid Nobiletin on Amplitude, Period, and Phase of the Circadian Clock Rhythm in PER2::LUCIFERASE Mouse Embryonic Fibroblasts.

    Ayako Shinozaki, Kenichiro Misawa, Yuko Ikeda, Atsushi Haraguchi, Mayo Kamagata, Yu Tahara, Shigenobu Shibata

    PloS one   12 ( 2 ) e0170904  2017  [Refereed]  [International journal]

     View Summary

    Flavonoids are natural polyphenols that are widely found in plants. The effects of flavonoids on obesity and numerous diseases such as cancer, diabetes, and Alzheimer's have been well studied. However, little is known about the relationships between flavonoids and the circadian clock. In this study, we show that continuous or transient application of flavonoids to the culture medium of embryonic fibroblasts from PER2::LUCIFERASE (PER2::LUC) mice induced various modifications in the circadian clock amplitude, period, and phase. Transient application of some of the tested flavonoids to cultured cells induced a phase delay of the PER2::LUC rhythm at the down slope phase. In addition, continuous application of the polymethoxy flavonoids nobiletin and tangeretin increased the amplitude and lengthened the period of the PER2::LUC rhythm. The nobiletin-induced phase delay was blocked by co-treatment with U0126, an ERK inhibitor. In summary, among the tested flavonoids, polymethoxy flavones increased the amplitude, lengthened the period, and delayed the phase of the PER2::LUC circadian rhythm. Therefore, foods that contain polymethoxy flavones may have beneficial effects on circadian rhythm disorders and jet lag.

    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  [Refereed]  [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

  • L-Ornithine affects peripheral clock gene expression in mice

    Takafumi Fukuda, Atsushi Haraguchi, Mari Kuwahara, Kaai Nakamura, Yutaro Hamaguchi, Yuko Ikeda, Yuko Ishida, Guanying Wang, Chise Shirakawa, Yoko Tanihata, Kazuaki Ohara, Shigenobu Shibata

    SCIENTIFIC REPORTS   6   34665  2016.10  [Refereed]

     View Summary

    The peripheral circadian clock is entrained by factors in the external environment such as scheduled feeding, exercise, and mental and physical stresses. In addition, recent studies in mice demonstrated that some food components have the potential to control the peripheral circadian clock during scheduled feeding, although information about these components remains limited. L-Ornithine is a type of non-protein amino acid that is present in foods and has been reported to have various physiological functions. In human trials, for example, L-ornithine intake improved a subjective index of sleep quality. Here we demonstrate, using an in vivo monitoring system, that repeated oral administration of L-ornithine at an early inactive period in mice induced a phase advance in the rhythm of PER2 expression. By contrast, L-ornithine administration to mouse embryonic fibroblasts did not affect the expression of PER2, indicating that L-ornithine indirectly alters the phase of PER2. L-Ornithine also increased plasma levels of insulin, glucose and glucagon-like peptide-1 alongside mPer2 expression, suggesting that it exerts its effects probably via insulin secretion. Collectively, these findings demonstrate that L-ornithine affects peripheral clock gene expression and may expand the possibilities of L-ornithine as a health food.

    DOI PubMed

  • In vitro and in vivo phase changes of the mouse circadian clock by oxidative stress

    Yu Tahara, Aya Yokota, Takuya Shiraishi, Shunya Yamada, Atsushi Haraguchi, Ayako Shinozaki, Shigenobu Shibata

    Journal of Circadian Rhythms   14 ( 1 ) 1 - 7  2016  [Refereed]

     View Summary

    Mammalian circadian rhythms are governed by an endogenous circadian clock system, including the molecular clock works in each cell and tissue. Adaptation of the circadian clock to different environmental stimuli such as light, food, and stress is essential for homeostasis maintenance. However, the influence of oxidative stress on the circadian clock phase is not fully understood in vitro and in vivo. Here, we examined the effects of hydrogen peroxide (H2O2)-induced oxidative stress on the PERIOD2::LUCIFERASE bioluminescence rhythm in mouse embryonic fibroblasts in vitro and in mouse peripheral tissues in vivo. The circadian clock phase changed with the dose of H2O2 and time of day in vitro
    similar phase changes were observed in vivo in the circadian clocks of the peripheral tissues. In addition, mice treated with hemin-induced oxidative stress also showed phase changes of peripheral clocks, similarly as H2O2 treatment. Thus, oxidative stress can entrain circadian clock systems.

    DOI

  • Antigen exposure in the late light period induces severe symptoms of food allergy in an OVA-allergic mouse model.

    Kana Tanabe, Eri Kitagawa, Misaki Wada, Atsushi Haraguchi, Kanami Orihara, Yu Tahara, Atsuhito Nakao, Shigenobu Shibata

    Scientific reports   5   14424 - 14424  2015.09  [Refereed]  [International journal]

     View Summary

    The mammalian circadian clock controls many physiological processes that include immune responses and allergic reactions. Several studies have investigated the circadian regulation of intestinal permeability and tight junctions known to be affected by cytokines. However, the contribution of circadian clock to food allergy symptoms remains unclear. Therefore, we investigated the role of the circadian clock in determining the severity of food allergies. We prepared an ovalbumin food allergy mouse model, and orally administered ovalbumin either late in the light or late in the dark period under light-dark cycle. The light period group showed higher allergic diarrhea and weight loss than the dark period group. The production of type 2 cytokines, IL-13 and IL-5, from the mesenteric lymph nodes and ovalbumin absorption was higher in the light period group than in the dark period group. Compared to the dark period group, the mRNA expression levels of the tight junction proteins were lower in the light period group. We have demonstrated that increased production of type 2 cytokines and intestinal permeability in the light period induced severe food allergy symptoms. Our results suggest that the time of food antigen intake might affect the determination of the severity of food allergy symptoms.

    DOI PubMed

  • Entrainment of mouse peripheral circadian clocks to <24 h feeding/fasting cycles under 24 h light/dark conditions.

    Yutaro Hamaguchi, Yu Tahara, Hiroaki Kuroda, Atsushi Haraguchi, Shigenobu Shibata

    Scientific reports   5   14207 - 14207  2015.09  [Refereed]  [International journal]

     View Summary

    The circadian clock system in peripheral tissues can endogenously oscillate and is entrained by the light-dark and fasting-feeding cycles in mammals. Although the system's range of entrainment to light-dark cycles with a non-24 h (<24 h) interval has been studied, the range of entrainment to fasting-feeding cycles with shorter periods (<24 h) has not been investigated in peripheral molecular clocks. In the present study, we measured this range by monitoring the mouse peripheral PER2::LUCIFERASE rhythm in vivo at different periods under each feeding cycle (Tau (T) = 15-24 h) under normal light-dark conditions. Peripheral clocks could be entrained to the feeding cycle with T = 22-24 h, but not to that with T = 15-21 h. Under the feeding cycle with T = 15-18 h, the peripheral clocks oscillated at near the 24-h period, suggesting that they were entrained to the light-dark cycle. Thus, for the first time, we demonstrated the range of entrainment to the non-24 h feeding cycle, and that the circadian range (T = 22-24 h) of feeding stimulus is necessary for peripheral molecular clock entrainment under light-dark cycles.

    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  [Refereed]  [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

  • Controlling access time to a high-fat diet during the inactive period protects against obesity in mice.

    Atsushi Haraguchi, Natsumi Aoki, Teiji Ohtsu, Yuko Ikeda, Yu Tahara, Shigenobu Shibata

    Chronobiology international   31 ( 8 ) 935 - 44  2014.10  [Refereed]  [International journal]

    Authorship:Lead author

     View Summary

    Free feeding (FF) with a high fat diet (HFD) causes excessive body weight gain, whereas restricted feeding (RF) with a HFD attenuates body weight gain. The effects of timing of feeding with a HFD (day vs. night) and feeding duration on energy homeostasis have not yet been investigated. In this study, we fed mice a HFD or a normal diet (ND) twice a day, during their active and inactive periods, on a schedule. The amount of food was regulated by feeding duration (2, 4 or 8 h). First, we investigated the effects of 4-h RF during active-inactive periods (ND-ND, HFD-HFD, ND-HFD or HFD-ND). Among all the 4-h RF groups, mice consumed almost the same amount of calories as those in the FF[ND] group, even those fed a HFD. Body weight and visceral fat in these three groups were lower than that in the FF[HFD] group. Second, we investigated the effects of RF duration. Body weight and visceral fat were higher in the 8-h groups than in the 4-h groups. Body weight and visceral fat were higher in the 2-h groups than in the 4-h groups even though the 2-h groups had less food. Third, we investigated the effects of eating a HFD during the inactive period, when RF duration was extended (2, 6 or 12 h). Mice were fed with a HFD during the inactive period for 2 h and fed with a ND during the active period for 2, 6 or 12 h. Body weight and visceral fat in these mice were comparable to those in the FF[ND] mice. The results of our first set of experiments suggest that 4-h RF was an adequate feeding duration to control the effect of a HFD on obesity. The results of our second set of experiments suggest 2-h RF (such as speed-eating) and 8-h RF, representative of eating disorders, are unhealthy feeding patterns related to obesity. The results of our third set of experiments suggest that eating a HFD for a short period during the night does not affect body weight and visceral fat. Taken together, these results indicate that consideration to feeding with a HFD during the inactive period and restricting eating habits relieve the risks of body weight gain and visceral fat accumulation.

    DOI PubMed

  • Warm water bath stimulates phase-shifts of the peripheral circadian clocks in PER2::LUCIFERASE mouse.

    Nobuaki Ohnishi, Yu Tahara, Daisuke Kuriki, Atsushi Haraguchi, Shigenobu Shibata

    PloS one   9 ( 6 ) e100272  2014  [Refereed]  [International journal]

     View Summary

    Circadian clocks in the peripheral tissues of mice are known to be entrained by pulse stimuli such as restricted feeding, novel wheel running, and several other agents. However, there are no reports on high temperature pulse-mediated entrainment on the phase-shift of peripheral clocks in vivo. Here we show that temperature treatment of mice for two days at 41°C, instead of 37°C, for 1-2 h during the inactive period, using a temperature controlled water bath stimulated phase-advance of peripheral clocks in the kidney, liver, and submandibular gland of PER2::LUCIFERASE mice. On the other hand, treatment for 2 days at 35°C ambient room temperature for 2 h did not cause a phase-advance. Maintenance of mice at 41°C in a water bath, sustained the core body temperature at 40-41°C. However, the use of 37°C water bath or the 35°C ambient room temperature elevated the core body temperature to 38.5°C, suggesting that at least a core body temperature of 40-41°C is necessary to cause phase-advance under light-dark cycle conditions. The temperature pulse stimulation at 41°C, instead of 37°C water bath for 2 h led to the elevated expression of Per1 and Hsp70 in the peripheral tissue of mice. In summary, the present study demonstrates that transient high temperature pulse using water bath during daytime causes phase-advance in mouse peripheral clocks in vivo. The present results suggest that hot water bath may affect the phase of peripheral clocks.

    DOI PubMed

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Books and Other Publications

  • 栄養学レビュー 第29巻2号 No.111

    原口 敦嗣( Part: Other, [特別論文]ストレスの多い職業人の心血管代謝疾患を予防する時間制限摂食:機構のレビュー)

    国際生命科学研究機構  2021.02

  • 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( Part: Contributor, 6章「食事のタイミングと時間栄養」)

    化学同人  2020.06 ISBN: 9784759820362

  • 特集1時間栄養学 ; 特集2乳幼児と超高齢者のための栄養学

    ( Part: Contributor, メンタルヘルスと摂食障害)

    講談社エディトリアル,講談社 (発売)  2020.01 ISBN: 9784065189115

  • 食行動と概日リズム調節機構

    柴田 重信, 池田 祐子, 原口 敦嗣( Part: Joint author)

    医薬ジャーナル社  2014.06

Misc

  • The effects of Polygalae Radix on clock gene expression rhythm and free-running period

    原口敦嗣, 斉藤恵祐, 田原優, 柴田重信

    時間生物学   26 ( 2 )  2020

    J-GLOBAL

  • ウロリチンAのPer2遺伝子発現リズムに対するインビトロ評価

    杜堯, 折原芳波, 原口敦嗣, 立石法史, 柴田重信

    日本栄養・食糧学会大会講演要旨集   74th   233 - 233  2020

    J-GLOBAL

  • Evaluate the effects of light, feeding, and stress that cause disturbance in peripheral clocks and locomotor activity rhythms due to social jetlag

    原口敦嗣, 田村好, 佐藤修平, 山崎智弘, 西村裕太郎, 福澤雅, 柴田重信

    時間生物学   25 ( 2 )  2019

    J-GLOBAL

  • Recovery effects of combination of caffeine and histidine on circadian clock system disturbed by social jetlag

    尾根田諭, 原口敦嗣, 石井裕也, 山崎智弘, 田村好, 佐藤脩平, 柴田重信

    時間生物学   25 ( 2 )  2019

    J-GLOBAL

  • 医療のさらなる安心・安全を志向する若手研究者のイノベーティブチャレンジ 時計遺伝子Per2の発現周期やマウス行動周期に対する遠志の影響について

    原口 敦嗣, 中村 文彬, 阿部 真太郎, 中尾 洋一, 柴田 重信

    日本薬学会年会要旨集   138年会 ( 1 ) 336 - 336  2018.03

  • 時計遺伝子Per2の発現周期やマウス行動周期に対する遠志の影響について

    原口敦嗣, 中村文彬, 阿部真太郎, 中尾洋一, 柴田重信

    日本薬学会年会要旨集(CD-ROM)   138th ( 1 ) 336 - 336  2018

    J-GLOBAL

  • 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   280  2018

    J-GLOBAL

  • フラボノイド系化合物の培養細胞下における体内時計への効果

    篠崎 綾子, 三澤 憲一郎, 池田 祐子, 原口 敦嗣, 鎌形 真世, 田原 優, 柴田 重信

    日本栄養・食糧学会大会講演要旨集   71回   339 - 339  2017.04

  • Potent effects of the flavonoid nobiletin on the amplitude, period, and phase of the circadian clock rhythm in PER2::LUCIFERASE mouse embryonic fibroblasts

    Ayako Shinozaki, Kenichiro Misawa, Yuko Ikeda, Atsushi Haraguchi, Mayo Kamagata, Yu Tahara, Shigenobu Shibata

    JOURNAL OF PHARMACOLOGICAL SCIENCES   133 ( 3 ) S204 - S204  2017.03

    Research paper, summary (international conference)  

  • EGCGの投与時刻の違いが糖負荷後の血糖値変動に及ぼす影響

    高橋 将記, 坪坂 美来, 原口 敦嗣, 池田 祐子, 柴田 重信

    日本栄養・食糧学会大会講演要旨集   70回   165 - 165  2016.04

  • 夜食症候群モデルマウスにおける脳内モノアミン概日リズム変動の特徴

    福澤雅, 原口敦嗣, 西村裕太郎, 岩見志保, 本橋弘章, 安田晋之介, 柴田重信

    日本栄養・食糧学会大会講演要旨集   70th   177  2016

    J-GLOBAL

  • Social jetlagの現状と課題 社会的時間と生体リズムの不調和 食事時間帯とsocial jetlag

    原口 敦嗣, 西村 裕太郎, 柴田 重信

    日本睡眠学会定期学術集会プログラム・抄録集   40回   110 - 110  2015.07

  • 【睡眠・眠りの基礎と臨床】 食行動と概日リズム調節機構

    柴田 重信, 池田 祐子, 原口 敦嗣

    医薬ジャーナル   50 ( 6 ) 1555 - 1559  2014.06

     View Summary

    視交叉上核(SCN)は、哺乳類における体内の生理現象を約24時間周期に調節している。食行動ホルモンと体内時計の研究は、マウスやラットを用いて盛んに行われている。オレキシンやグレリン等の食欲増進ホルモンや、レプチン等の食欲抑制ホルモンも、SCNの支配を受けて日内リズムを刻むことで、食行動にもリズム性が生じることが分かってきた。さらにヒトを対象とした研究により、食事の摂り方によって食欲ホルモン分泌が変化し、肥満に関与していることが明らかとなった。近年、ヒトの体内時計の測定手法が確立されたことから、ヒトを対象とした食欲ホルモンと体内時計の研究の発展が期待される。(著者抄録)

  • 食行動と概日リズム調節機構 (特集 睡眠・眠りの基礎と臨床)

    柴田 重信, 池田 祐子, 原口 敦嗣

    医薬ジャーナル   50 ( 6 ) 69 - 73  2014.06

    CiNii

  • Restraint stress strongly disturbs the mouse circadian clock systems

    Yu Tahara, Takuya Shiraishi, Yosuke Kikuchi, Nobuaki Onishi, Shun-ya Yamada, Atsushi Haraguchi, Daisuke Kuriki, Shigenobu Shibata

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   206P - 206P  2014

    Research paper, summary (international conference)  

  • 高脂肪食の摂取時刻や摂取タイミングによる体重や脂肪率、末梢時計への影響

    原口 敦嗣, 青木 菜摘, 大津 定治, 柴田 重信

    日本栄養・食糧学会大会講演要旨集   67回   213 - 213  2013.04

  • High fat diet feeding duration and time dependent impairment of energy homeostasis and peripheral clock phase

    Atsushi Haraguchi, Natsumi Aoki, Teiji Ohtsu, Shigenobu Shibata

    JOURNAL OF PHYSIOLOGICAL SCIENCES   63   S282 - S282  2013

    Research paper, summary (international conference)  

  • マウスを用いた時間栄養学視点からの塩分摂取と排泄機構の研究

    柴田重信, 青木菜摘, 濱口雄太郎, 原口敦嗣

    ソルト・サイエンス研究財団助成研究報告集 2 医学 食品科学編   2011   229 - 236  2013

    J-GLOBAL

  • 拘束ストレスは強い末梢時計同調効果を持つ

    白石卓也, 田原優, 菊池耀介, 大西信明, 原口敦嗣, 栗城大輔, 柴田重信

    時間生物学   19 ( 2 ) 164  2013

    J-GLOBAL

  • シフトワークモデルマウスの様態観察と時間栄養学的治療法の確立

    田原優, 濱口雄太郎, 一杉真史, 黒田大暁, 原口敦嗣, 柴田重信

    日本分子生物学会年会プログラム・要旨集(Web)   35th   3W11III-3 (WEB ONLY)  2012

    J-GLOBAL

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Awards

  • アーリーバードプログラム

    2020.05   早稲田大学 理工学術院総合研究所 若手研究者支援事業  

  • 若手研究助成

    2020.01   公益財団法人ダノン健康栄養財団  

  • Best Poster Award

    2019.04   World Congress of Chronobiology  

    Winner: Atsushi Haraguchi

  • travel grant

    2018.07   Asian Forum on Chronobiology and Sapporo Symposium on Biological Rhythm  

    Winner: Atsushi Haraguchi

  • アーリーバードプログラム

    2018.05   早稲田大学 理工学術院総合研究所 若手研究者支援事業  

  • Poster Prize 2017

    2017.08   European Biological Rhythms Society Congress  

    Winner: Atsushi Haraguchi

  • Poster Award

    2016.11   Japanese Society for Chronobiology  

    Winner: Atsushi Haraguchi

  • Junior Investigator’s Award

    2013.03   The Physiological Sciety of Japan  

    Winner: Atsushi Haraguchi

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Research Projects

  • Mechanisms underlying aging and disease related circadian dysfunctions by in vivo Miniscope

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

    Project Year :

    2020.10
    -
    2024.03
     

  • 概日時計と腸内細菌叢の観点からみた食欲調節メカニズムの解明

    日本学術振興会  科学研究費助成事業 若手研究

    Project Year :

    2019.04
    -
    2022.03
     

    原口 敦嗣

     View Summary

    本研究は、食欲制御に関与する新たなメカニズム解明を概日時計と腸内細菌叢の観点から行うことを目的としている。先行研究により、腸内細菌叢が活性化することで生成されるSCFA(短鎖脂肪酸)の一つである酢酸の血中濃度が上昇することで食欲が抑制されることや、食欲が概日時計に制御されており日内変動を示すことなどが報告されている。食欲制御に関与している概日時計と腸内細菌叢はお互いに相互作用しており、宿主の概日時計の影響を受けて腸内細菌叢の構成やSCFA量が日内変動することや、腸内細菌が減少することで宿主の末梢時計などの概日リズム性が低下することが報告されている。以上のような報告はあるものの、実際に腸内菌叢改善作用を有する食品を用いて腸内環境改善を介した食欲抑制効果の報告はほとんど無い。そこで、1年目である2019年度は腸内菌叢改善作用を有する食品素材である難消化性デキストリン(RM)を高脂肪食(HFD)に添加して使用することで、長期的なRM摂取により食欲抑制が生じるか(実験1)、また長期的なRM摂取により腸内環境が改善しているか(実験2)について調べることとした。
    本実験はマウスを用いて行い、HFDを給餌する対照群とHFDにRMを添加したRM群の2群を準備して実験を行った。実験1では、各餌を8週間給餌し、その間の摂食量や体重の測定、および給餌開始後2週、4週、8週目に盲腸内pHの測定や盲腸内容物の採取をに行った。その結果、RM群の盲腸内pHは対照群と比較して4週目以降低下している(腸内細菌叢が活性化することでSCFAが生成され、pHが低下したと考えられる)ことが確認された。また、実験2では実験1で採取した盲腸内容物を用いてSCFA量の測定を行なったが、まだ結果がまとまっていない。以上のことから、RMの長期摂取により腸内環境の改善を通して食欲が制御されていることが示唆された。

  • 食欲制御に対する概日時計・腸内細菌叢の貢献度の検証

    早稲田大学 理工学術院総合研究所  若手研究者支援事業 アーリーバード

    Project Year :

    2020.05
    -
    2021.03
     

  • 食事タイミングとうつ症状発症のメカニズム解明

    公益財団法人ダノン健康栄養財団  若手研究助成

    Project Year :

    2020.01
    -
    2020.12
     

  • カフェインの摂取時刻による抗肥満効果に対する時間栄養学的検証

    早稲田大学 理工学術院総合研究所  若手研究者支援事業 アーリーバード

    Project Year :

    2018.05
    -
    2019.03
     

    原口 敦嗣

  • 食生活の乱れとうつ病発症の関連とメカニズムの解明

    日本学術振興会  科学研究費助成事業 特別研究員奨励費

    Project Year :

    2017.04
    -
    2019.03
     

    原口 敦嗣

     View Summary

    夕食後から入眠までの間に食事を摂取する「夜食症候群」の患者は、通常のうつ患者とは違い夕方から夜にかけてうつ症状を示すことが知られている。申請者は乱れた食事タイミングがうつ症状発症の原因になるのではないかと考え、後述する給餌条件を用いて仮説の検証と発症メカニズムの解明を行うことを本研究の目的とした。本研究では、通常食を自由摂食させつつ、高脂肪食を明期(マウスにとっての非活動期)の真ん中に5分間給餌する条件下で飼育されたマウスを食事タイミングの乱れたマウスとし、通常食を自由摂食させる群を対照群として実験を行った。前年度までの研究により、このモデル群が夜食症候群の患者と同様に時刻特異的なうつ症状を示すこと、末梢時計の位相変動を引き起こすほどのカロリー量の摂取や海馬におけるセロトニンのストレス応答性の変化が原因となることが分かった。そこで本年度はさらなるメカニズムの解明を行うために時刻依存的うつ様行動に関与しているセロトニン受容体の特定とスクリーニングされた受容体の遺伝子発現量の海馬における時刻推移に関する検証を行なった。実験1では、先行研究によりうつ様行動を改善することが報告されている各セロトニン受容体の作動薬もしくは拮抗薬をNESモデルマウスに投与して時刻依存的なうつ様行動について検証した。その結果、ある受容体(受容体A)の作動薬のみが改善作用を示すことが分かった。実験2では、対照群とNESモデル群から海馬のサンプルを採取してリアルタイムRT-PCRにより、セロトニン受容体AのmRNA量の日内変動について検証を行った。その結果、セロトニン受容体AのmRNA発現量の日内変動が確認されなかった。以上の実験結果から、乱れた食事タイミング・パターンが時刻特異的うつ様行動を引き起こすメカニズムとして、セロトニン受容体Aの機能が低下していることが確認された。

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Specific Research

  • 各食事の摂取カロリー割合による体重増加への影響に関する検証

    2021  

     View Summary

    当研究室のヒトを対象とした中規模調査により、昼食のカロリー摂取割合が多いヒトほど体重が重いこと、特に女性でその特徴が顕著であることが分かったため、マウスでも同様の傾向が確認できるのか、またできた場合はそのような現象がなぜ生じるのか調べた。その結果、ヒトと同様に、雌マウスでは昼食に多くの餌を摂取する昼食群の体重が朝食群や対照群と比較して優位に増加し、夕食群よりも増加していることが確認できた。一方、雄マウスでは対照群と朝食群、昼食群、夕食群の順で体重が増加しており、ヒトを対象とした調査で確認できたような特徴は確認できなかった。今後は、認知機能などへの影響についても検証していこうと考えている。

  • セロトニン受容体に着目した食事タイミングの乱れによるうつ症状誘発のメカニズム解明

    2020  

     View Summary

     食事タイミングの乱れた夜食症候群や睡眠関連摂食障害の患者の多くがうつ症状を示すことが知られていることから、食事タイミングの乱れがうつ症状誘発に関与している可能性が示唆でき、実際に申請者はマウスを用いた実験から食事タイミングの乱れがうつ様行動を誘発すること、海馬においてCREBのリン酸化率が低下していることを確認している。本年度実施の研究により、ある受容体を刺激することでCREBのリン酸化率が改善し、うつ様行動も改善されることが分かった。今後はさらなるメカニズム解明を行う予定である。

  • セロトニン受容体を介した食事タイミングの乱れによるうつ症状誘発のメカニズム解明

    2019  

     View Summary

     食事タイミングの乱れた夜食症候群や睡眠関連摂食障害の患者の多くがうつ症状を示すことが知られていることから、食事タイミングの乱れがうつ症状誘発に関与している可能性が示唆でき、実際に申請者はマウスを用いた実験からこれらの関連性について既に確認している。そこで本研究では、食事タイミングを乱した給餌条件下で飼育したマウスを用いて、セロトニン受容体やCREBなどのうつ症状に関与するタンパク質の発現量を海馬のサンプルを用いて測定した。その結果、乱れた食事タイミングによりCREBのリン酸化率が低下していることが確認された。今後は、さらなるメカニズム解明を行う予定である。

 

Syllabus

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Teaching Experience

  • Advanced Life Science

    Waseda University  

    2019.04
    -
    Now
     

  • Laboratory for Advanced Science and Engineering 1B

    Waseda University  

    2019.04
    -
    Now
     

  • Laboratory for Advanced Science and Engineering 1A

    Waseda University  

    2019.04
    -
    Now
     

 

Committee Memberships

  • 2019.04
    -
    Now

    日本時間生物学会  評議員

Social Activities

  • 現代の生命科学

    早稲田大学高等学院 

    2016.10
    -
     

Academic Activities

  • TSEF2021

    Competition, symposium, etc.

    早稲田大学高等学院  

    2021.03
    -