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Shigenobu Shibata - One of the best experts on this subject based on the ideXlab platform.
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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
Chronobiology International, 2021Co-Authors: Atsushi Haraguchi, Yu Tahara, Yosuke Kikuchi, Miyabi Fukuzawa, Yutaro Nishimura, Shigenobu ShibataAbstract:Social jetlag (SJL) is defined as the discrepancy between social and biological rhythms and calculated by the difference between the midpoint of sleep time on working-days and free-days. Previous h...
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Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue
Scientific Reports, 2018Co-Authors: Yu Tahara, Atsushi Haraguchi, Yuko Ikeda, Mayu Yamazaki, Hiroaki Motohashi, Hiroyuki Sasaki, Haruna Sukigara, Hiroki Miyakawa, Shinji Fukuda, Shigenobu ShibataAbstract: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.
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night eating model shows time specific depression like behavior in the forced swimming test
Scientific Reports, 2018Co-Authors: Atsushi Haraguchi, Yu Tahara, Hiroaki Motohashi, Shiho Iwami, Miyabi Fukuzawa, Yutaro Nishimura, Shigenobu ShibataAbstract: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.
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forced rather than voluntary exercise entrains Peripheral Clocks via a corticosterone noradrenaline increase in per2 luc mice
Scientific Reports, 2016Co-Authors: Hiroyuki Sasaki, Yuko Ikeda, Yu Tahara, Mayo Kamagata, Yuta Hattori, Shinnosuke Yasuda, Shiho Iwami, Shigenobu ShibataAbstract: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.
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time restricted feeding of rapidly digested starches causes stronger entrainment of the liver Clock in per2 luciferase knock in mice
Nutrition Research, 2013Co-Authors: Misa Itokawa, Hiroki Nagahama, Teiji Ohtsu, Naoki Furutani, Akiko Hirao, Makiko Otsuka, Kazuko Hirao, Tamao Hatta, Shigenobu ShibataAbstract:Restricting feeding to daytime can entrain circadian Clocks in Peripheral organs of rodents, and nutrients that rapidly increase the blood glucose level are suitable for inducing entrainment. However, dietetic issues, for example, whether or not the diet comprises heated food, have not been fully explored. We therefore hypothesized that rapidly digested starch causes stronger entrainment than slowly digested starch. The entrainment ability of the liver Clock in PER2::LUCIFERASE knock-in mice, blood glucose levels, insulin levels, and acute changes in liver Clock gene expression were compared between a β-starch (native)-substituted AIN-93M standard diet and an α-starch (gelatinized)-substituted diet. β-Corn and β-rice starch induced larger phase delays of the liver Clock, larger blood glucose increases, and higher Per2 gene expression in the liver compared with β-potato starch. Starch granule size, as examined by electron microscopy, was larger for β-potato starch than for β-corn or β-rice starch. After heating, we obtained gelatinized α-potato, α-corn, and α-rice starch, which showed destruction of the crystal structure and a high level of gelatinization. No difference in the increase of blood glucose or insulin levels was observed between β-corn and α-corn starch, or between β-rice and α-rice starch. In contrast, α-potato starch caused higher levels of glucose and insulin compared with β-potato starch. An α-potato starch-substituted diet induced larger phase delays of the liver Clock than did β-potato starch. Therefore, rapidly digested starch is appropriate for Peripheral Clock entrainment. Dietetic issues (heated vs unheated) are important when applying basic mouse data to humans.
Ioannis P Androulakis - One of the best experts on this subject based on the ideXlab platform.
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modeling the influence of seasonal differences in the hpa axis on synchronization of the circadian Clock and cell cycle
Endocrinology, 2018Co-Authors: Kamau Pierre, Rohit T Rao, Clara Hartmanshenn, Ioannis P AndroulakisAbstract:Synchronization of biological functions to environmental signals enables organisms to anticipate and appropriately respond to daily external fluctuations and is critical to the maintenance of homeostasis. Misalignment of circadian rhythms with environmental cues is associated with adverse health outcomes. Cortisol, the downstream effector of hypothalamic-pituitary-adrenal (HPA) activity, facilitates synchronization of Peripheral biological processes to the environment. Cortisol levels exhibit substantial seasonal rhythmicity, with peak levels occurring during the short-photoperiod winter months and reduced levels occurring in the long-photoperiod summer season. Seasonal changes in cortisol secretion could therefore alter its entraining capabilities, resulting in a season-dependent modification in the alignment of biological activities with the environment. We develop a mathematical model to investigate the influence of photoperiod-induced seasonal differences in the circadian rhythmicity of the HPA axis on the synchronization of the Peripheral circadian Clock and cell cycle in a heterogeneous cell population. Model simulations predict that the high-amplitude cortisol rhythms in winter result in the greatest entrainment of Peripheral oscillators. Furthermore, simulations predict a circadian gating of the cell cycle with respect to the expression of Peripheral Clock genes. Seasonal differences in cortisol rhythmicity are also predicted to influence mitotic synchrony, with a high-amplitude winter rhythm resulting in the greatest synchrony and a shift in timing of the cell cycle phases, relative to summer. Our results highlight the primary interactions among the HPA axis, the Peripheral circadian Clock, and the cell cycle and thereby provide an improved understanding of the implications of circadian misalignment on the synchronization of Peripheral regulatory processes.
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mathematical modeling of light mediated hpa axis activity and downstream implications on the entrainment of Peripheral Clock genes
Physiological Genomics, 2014Co-Authors: Panteleimon D Mavroudis, Steve E Calvano, Siobhan A Corbett, Ioannis P AndroulakisAbstract:In this work we propose a semimechanistic model that describes the photic signal transduction to the hypothalamic-pituitary-adrenal (HPA) axis that ultimately regulates the synchronization of perip...
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entrainment of Peripheral Clock genes by cortisol
Physiological Genomics, 2012Co-Authors: Panteleimon D Mavroudis, Jeremy D Scheff, Steve E Calvano, Stephen F Lowry, Ioannis P AndroulakisAbstract:Circadian rhythmicity in mammals is primarily driven by the suprachiasmatic nucleus (SCN), often called the central pacemaker, which converts the photic information of light and dark cycles into neuronal and hormonal signals in the periphery of the body. Cells of Peripheral tissues respond to these centrally mediated cues by adjusting their molecular function to optimize organism performance. Numerous systemic cues orchestrate Peripheral rhythmicity, such as feeding, body temperature, the autonomic nervous system, and hormones. We propose a semimechanistic model for the entrainment of Peripheral Clock genes by cortisol as a representative entrainer of Peripheral cells. This model demonstrates the importance of entrainer's characteristics in terms of the synchronization and entrainment of Peripheral Clock genes, and predicts the loss of intercellular synchrony when cortisol moves out of its homeostatic amplitude and frequency range, as has been observed clinically in chronic stress and cancer. The model also predicts a dynamic regime of entrainment, when cortisol has a slightly decreased amplitude rhythm, where individual Clock genes remain relatively synchronized among themselves but are phase shifted in relation to the entrainer. The model illustrates how the loss of communication between the SCN and Peripheral tissues could result in desynchronization of Peripheral Clocks.
Katsutaka Oishi - One of the best experts on this subject based on the ideXlab platform.
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disrupted light dark cycle abolishes circadian expression of Peripheral Clock genes without inducing behavioral arrhythmicity in mice
Biochemical and Biophysical Research Communications, 2015Co-Authors: Katsutaka Oishi, Sayaka Higoyamamoto, Saori Yamamoto, Yuki YasumotoAbstract:Abstract The environmental light–dark (LD) cycle entrains the central circadian Clock located in the suprachiasmatic nucleus (SCN) of mammals. The present study examined the effects of disrupted LD cycles on Peripheral Clocks in mice housed under a normal 12 h light-12 h dark cycle (LD 12:12) or an ultradian LD 3:3 cycle. Drinking behavior seemed to be free-running with a long period (26.03 h) under ultradian LD 3:3 cycles, in addition to light-induced direct suppression (masking effect). Core body temperature completely lost robust circadian rhythm and acquired a 6-h rhythm with a low amplitude under LD 3:3. Robust circadian expression of Per1, Per2, Clock and Bmal1 mRNAs was similarly flattened to intermediate levels in the liver, heart and white adipose tissue under LD 3:3. Robust circadian expression of Rev-erbα mRNA was completely damped in these tissues. Circadian expression of Dbp, a Clock-controlled gene, was also disrupted in these tissues from mice housed under LD 3:3. The aberrant LD cycle seemed to induce the loss of circadian gene expression at the level of transcription, because rhythmic pre-mRNA expression of these genes was also abolished under LD 3:3. In addition to the direct effect of the aberrant LD cycle, abolished systemic time cues such as those of plasma corticosterone and body temperature might be involved in the disrupted expression of these circadian genes under LD 3:3. Our findings suggest that disrupted environmental LD cycles abolish the normal oscillation of Peripheral Clocks and induce internal desynchrony in mammals.
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disruption of behavioral circadian rhythms induced by psychophysiological stress affects plasma free amino acid profiles without affecting Peripheral Clock gene expression in mice
Biochemical and Biophysical Research Communications, 2014Co-Authors: Katsutaka Oishi, Saori Yamamoto, Nanako Itoh, Koyomi Miyazaki, Tadashi Nemoto, Yasukazu Nakakita, Hirotaka KanedaAbstract:Abstract Disordered circadian rhythms are associated with various psychiatric conditions and metabolic diseases. We recently established a mouse model of a psychophysiological stress-induced chronic sleep disorder (CSD) characterized by reduced amplitude of circadian wheel-running activity and sleep–wake cycles, sleep fragmentation and hyperphagia. Here, we evaluate day–night fluctuations in plasma concentrations of free amino acids (FAA), appetite hormones and prolactin as well as the hepatic expression of circadian Clock-related genes in mice with CSD (CSD mice). Nocturnal increases in wheel-running activity and circadian rhythms of plasma prolactin concentrations were significantly disrupted in CSD mice. Hyperphagia with a decreased leptin/ghrelin ratio was found in CSD mice. Day–night fluctuations in plasma FAA contents were severely disrupted without affecting total FAA levels in CSD mice. Nocturnal increases in branched-chain amino acids such as Ile, Leu, and Val were further augmented in CSD mice, while daytime increases in Gly, Ala, Ser, Thr, Lys, Arg, His, Tyr, Met, Cys, Glu, and Asn were significantly attenuated. Importantly, the circadian expression of hepatic Clock genes was completely unaffected in CSD mice. These findings suggest that circadian Clock gene expression does not always reflect disordered behavior and sleep rhythms and that plasma FFA profiles could serve as a potential biomarker of circadian rhythm disorders.
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thrombomodulin is a Clock controlled gene in vascular endothelial cells
Journal of Biological Chemistry, 2007Co-Authors: Norihiko Takeda, Koji Maemura, Shuichi Horie, Katsutaka Oishi, Yasushi Imai, Tomohiro Harada, Tetsuya Saito, Taro Shiga, Eisuke Amiya, Ichiro ManabeAbstract:Cardiovascular diseases are closely related to circadian rhythm, which is under the control of an internal biological Clock mechanism. Although a biological Clock exists not only in the hypothalamus but also in each Peripheral tissue, the biological relevance of the Peripheral Clock remains to be elucidated. In this study we searched for Clock-controlled genes in vascular endothelial cells using microarray technology. The expression of a total of 229 genes was up-regulated by Clock/BMAL2. Among the genes that we identified, we examined the thrombomodulin (TM) gene further, because TM is an integral membrane glycoprotein that is expressed primarily in vascular endothelial cells and plays a major role in the regulation of intravascular coagulation. TM mRNA and protein expression showed a clear circadian oscillation in the mouse lung and heart. Reporter analyses, gel shift assays, and chromatin immunoprecipitation analyses using the TM promoter revealed that a heterodimer of Clock and BMAL2 binds directly to the E-box of the TM promoter, resulting in TM promoter transactivation. Indeed, the oscillation of TM gene expression was abolished in Clock mutant mice, suggesting that TM expression is regulated by the Clock gene in vivo. Finally, the phase of circadian oscillation of TM mRNA expression was altered by temporal feeding restriction, suggesting TM gene expression is regulated by the Peripheral Clock system. In conclusion, these data suggest that the Peripheral Clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events.
Yuko Ikeda - One of the best experts on this subject based on the ideXlab platform.
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Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue
Scientific Reports, 2018Co-Authors: Yu Tahara, Atsushi Haraguchi, Yuko Ikeda, Mayu Yamazaki, Hiroaki Motohashi, Hiroyuki Sasaki, Haruna Sukigara, Hiroki Miyakawa, Shinji Fukuda, Shigenobu ShibataAbstract: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.
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potent synchronization of Peripheral circadian Clocks by glucocorticoid injections in per2 luc Clock Clock mice
Chronobiology International, 2017Co-Authors: Mayo Kamagata, Yuko Ikeda, Hiroyuki Sasaki, Yuta Hattori, Shinnosuke Yasuda, Shiho Iwami, Miku Tsubosaka, Ryosuke Ishikawa, Ai Todoh, Konomi TamuraAbstract: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.
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l-Ornithine affects Peripheral Clock gene expression in mice.
Scientific Reports, 2016Co-Authors: Takafumi Fukuda, Atsushi Haraguchi, Mari Kuwahara, Kaai Nakamura, Yutaro Hamaguchi, Guanying Wang, Chise Shirakawa, Yuko Ikeda, Yuko Ishida, Yoko TanihataAbstract: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.
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forced rather than voluntary exercise entrains Peripheral Clocks via a corticosterone noradrenaline increase in per2 luc mice
Scientific Reports, 2016Co-Authors: Hiroyuki Sasaki, Yuko Ikeda, Yu Tahara, Mayo Kamagata, Yuta Hattori, Shinnosuke Yasuda, Shiho Iwami, Shigenobu ShibataAbstract: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.
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fish oil accelerates diet induced entrainment of the mouse Peripheral Clock via gpr120
PLOS ONE, 2015Co-Authors: Akiko Furutani, Yuko Ikeda, Misa Itokawa, Hiroki Nagahama, Teiji Ohtsu, Naoki Furutani, Mayo Kamagata, Zhihong Yang, Akira Hirasawa, Yu TaharaAbstract:The circadian Peripheral Clock is entrained by restricted feeding (RF) at a fixed time of day, and insulin secretion regulates RF-induced entrainment of the Peripheral Clock in mice. Thus, carbohydrate-rich food may be ideal for facilitating RF-induced entrainment, although the role of dietary oils in insulin secretion and RF-induced entrainment has not been described. The soybean oil component of standard mouse chow was substituted with fish or soybean oil containing docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA). Tuna oil (high DHA/EPA), menhaden oil (standard), and DHA/EPA dissolved in soybean oil increased insulin secretion and facilitated RF-induced phase shifts of the liver Clock as represented by the bioluminescence rhythms of PER2::LUCIFERASE knock-in mice. In this model, insulin depletion blocked the effect of tuna oil and fish oil had no effect on mice deficient for GPR120, a polyunsaturated fatty acid receptor. These results suggest food containing fish oil or DHA/EPA is ideal for adjusting the Peripheral Clock.
Yu Tahara - One of the best experts on this subject based on the ideXlab platform.
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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
Chronobiology International, 2021Co-Authors: Atsushi Haraguchi, Yu Tahara, Yosuke Kikuchi, Miyabi Fukuzawa, Yutaro Nishimura, Shigenobu ShibataAbstract:Social jetlag (SJL) is defined as the discrepancy between social and biological rhythms and calculated by the difference between the midpoint of sleep time on working-days and free-days. Previous h...
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neuronal pas domain 2 npas2 facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism
Biomaterials, 2019Co-Authors: Hodaka Sasaki, Akishige Hokugo, Kenzo Morinaga, Hiroko Okawa, Sil Park, Yu Tahara, Christopher S ColwellAbstract:Titanium (Ti) biomaterials have been applied to a wide range of implantable medical devices. When placed in bone marrow, Ti-biomaterials integrate to the surrounding bone tissue by mechanisms that are not fully understood. We have previously identified an unexpected upregulation of circadian Clock molecule neuronal PAS domain 2 (Npas2) in successfully integrated implant with a rough surface. This study aimed to elucidate the molecular mechanism of osseointegration through determining the role of Npas2. Human bone marrow stromal cells (BMSC) that were cultured on a Ti disc with SLA surface exhibited increased NPAS2 expression compared to BMSC cultured on a machined surface. A mouse model was developed in which miniature Ti implants were surgically placed into femur bone marrow. The implant push-out test and bone-to-implant contact measurements demonstrated the establishment of osseointegration in 3 weeks. By contrast, in Npas2 functional knockout (KO) mice, the implant push-out value measured for SLA surface Ti implant was significantly decreased. Npas2 KO mice demonstrated normal femur bone structure surrounding the Ti implant; however, the recovered implants revealed abnormal remnant mineralized tissue, which lacked dense collagen architecture typically found on recovered implants from wild type mice. To explore the mechanisms leading to the induced Npas2 expression, an unbiased chemical genetics analysis was conducted using mouse BMSC carrying an Npas2-reporter gene for high throughput screening of Library of Pharmacologically Active Compounds. Npas2 modulating compounds were found clustered in regulatory networks of the α2-adrenergic receptor and its downstream cAMP/CREB signaling pathway. Mouse primary BMSC exposed to SLA Ti disc significantly increased the expression of α2-adrenergic receptors, but the expression of β2-adrenergic receptor was unaffected. Our data provides the first evidence that Peripheral Clock gene component Npas2 plays a role in facilitating the enhanced osseointegration through neuroskeletal regulatory pathways induced by BMSC in contact with rough surface Ti implant.
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Gut Microbiota-Derived Short Chain Fatty Acids Induce Circadian Clock Entrainment in Mouse Peripheral Tissue
Scientific Reports, 2018Co-Authors: Yu Tahara, Atsushi Haraguchi, Yuko Ikeda, Mayu Yamazaki, Hiroaki Motohashi, Hiroyuki Sasaki, Haruna Sukigara, Hiroki Miyakawa, Shinji Fukuda, Shigenobu ShibataAbstract: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.
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night eating model shows time specific depression like behavior in the forced swimming test
Scientific Reports, 2018Co-Authors: Atsushi Haraguchi, Yu Tahara, Hiroaki Motohashi, Shiho Iwami, Miyabi Fukuzawa, Yutaro Nishimura, Shigenobu ShibataAbstract: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.
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age related circadian disorganization caused by sympathetic dysfunction in Peripheral Clock regulation
npj Aging and Mechanisms of Disease, 2017Co-Authors: Yu Tahara, Atsushi Haraguchi, Yuta Takatsu, Takuya Shiraishi, Yosuke Kikuchi, Mayu Yamazaki, Hiroaki Motohashi, Aya Muto, Hiroyuki Sasaki, Daisuke KurikiAbstract: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.