研究者詳細 - 木内　謙一郎

論文 - 木内　謙一郎

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Transient Dexamethasone Loading Induces Prolonged Hyperglycemia in Male Mice with Histone Acetylation in Dpp-4 Promoter

Uto A., Miyashita K., Endo S., Sato M., Ryuzaki M., Kinouchi K., Mitsuishi M., Meguro S., Itoh H.

Endocrinology (United States) （Endocrinology (United States)） 162 （ 12 ） 2021年12月

ISSN 00137227

Glucocorticoid causes hyperglycemia, which is common in patients with or without diabetes. Prolonged hyperglycemia can be experienced even after the discontinuation of glucocorticoid use. In the present study, we examined the time course of blood glucose level in hospital patients who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance tests, level of insulin and glucagon-like peptide 1 (GLP-1), and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.

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Pharmacokinetics of hydrogen after ingesting a hydrogen-rich solution: A study in pigs

Ichihara G., Katsumata Y., Moriyama H., Kitakata H., Hirai A., Momoi M., Ko S., Shinya Y., Kinouchi K., Kobayashi E., Sano M.

Heliyon （Heliyon） 7 （ 11 ） 2021年11月

ISSN 24058440

Drinking hydrogen (H2)-rich water is a common way to consume H2. Although many studies have shown efficacy of drinking H2-rich water in neuropsychiatric and endocrine metabolic disorders, their authenticity has been questioned because none examined the associated pharmacokinetics of H2. Therefore, we performed the first study to investigate the pharmacokinetics of H2 in pigs given an H2-rich glucose solution with the aim to extrapolate the findings to humans. We inserted blood collection catheters into the jejunal and portal veins, suprahepatic inferior vena cava, and carotid artery of 4 female pigs aged 8 weeks. Then, within 2 min we infused 500 ml of either H2-rich or H2-free glucose solution into the jejunum via a percutaneous gastrostomy tube and measured changes in H2 concentration in venous and arterial blood over 120 min. After infusion of the H2-rich glucose solution, H2 concentration in the portal vein peaked at 0.05 mg/L and remained at more than 0.016 mg/L (H2 saturation level, 1%) after 1 h; it also increased after infusion of H2-free glucose solution but remained below 0.001 mg/L (H2 saturation level, 0.06%). We assume that H2 was subsequently metabolized in the liver or eliminated via the lungs because it was not detected in the carotid artery. In conclusion, drinking highly concentrated H2-rich solution within a short time is a good way to increase H2 concentration in portal blood and supply H2 to the liver.

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Circadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies

Kinouchi K., Mikami Y., Kanai T., Itoh H.

Molecular Aspects of Medicine （Molecular Aspects of Medicine） 80 2021年08月

ISSN 00982997

Creatures on earth have the capacity to preserve homeostasis in response to changing environments. The circadian clock enables organisms to adapt to daily predictable rhythms in surrounding conditions. In mammals, circadian clocks constitute hierarchical network, where the central pacemaker in hypothalamic suprachiasmatic nucleus (SCN) serves as a time-keeping machinery and governs peripheral clocks in every other organ through descending neural and humoral factors. The central clock in SCN is reset by light, whilst peripheral clocks are entrained by feeding-fasting rhythms, emphasizing the point that temporal patterns of nutrient availability specifies peripheral clock functions. Indeed, emerging evidence revealed various types of diets or timing of food intake reprogram circadian rhythms in a tissue specific manner. This advancement in understanding of mechanisms underlying tissue specific responsiveness of circadian oscillators to nutrients at the genomic and epigenomic levels is largely owing to employment of state-of-the-art technologies. Specifically, high-throughput transcriptome, proteome, and metabolome have provided insights into how genes, proteins, and metabolites behave over circadian cycles in a given tissue under a certain dietary condition in an unbiased fashion. Additionally, combinations with specialized types of sequencing such as nascent-seq and ribosomal profiling allow us to dissect how circadian rhythms are generated or obliterated at each step of gene regulation. Importantly, chromatin immunoprecipitation followed by deep sequencing methods provide chromatin landscape in terms of regulatory mechanisms of circadian gene expression. In this review, we outline recent discoveries on temporal genomic and epigenomic regulation of circadian rhythms, discussing entrainment of the circadian rhythms by feeding as a fundamental new comprehension of metabolism and immune response, and as a potential therapeutic strategy of metabolic and inflammatory diseases.

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Combined Gene Expression and Chromatin Immunoprecipitation From a Single Mouse Hippocampus

Helbling J.C., Kinouchi K., Trifilieff P., Sassone-Corsi P., Moisan M.P.

Current Protocols （Current Protocols） 1 （ 2 ） 2021年02月

All neuronal cells hold the same genetic information but vary by their structural and functional plasticity depending on the brain area and environmental influences. Such variability involves specific gene regulation, which is driven by transcription factors (TFs). In the field of neuroscience, epigenetics is the main mechanism that has been investigated to understand the dynamic modulation of gene expression by behavioral responses, stress responses, memory processes, etc. Nowadays, gene expression analyzed by real-time quantitative PCR and TF binding estimated by chromatin immunoprecipitation (ChIP) enables one to dissect this regulation. Because of the wide range of transgenic models, as well as cost-effective aspects, mouse models are widely used neuroscience. Thus, we have set up a protocol that allows extraction of both RNA for gene expression analysis and chromatin for ChIP experiment from a single mouse hippocampus. Using such protocols, information regarding gene expression and regulatory molecular mechanisms from the same animal can be integrated and correlated with neurobiological and behavioral outcomes. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Hippocampus isolation from mouse brain. Basic Protocol 2: RNA extraction and gene expression analysis from a mouse half hippocampus. Basic Protocol 3: ChIP from one hemisphere side mouse hippocampus.

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S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling

Greco C.M., Cervantes M., Fustin J.M., Ito K., Ceglia N., Samad M., Shi J., Koronowski K.B., Forne I., Ranjit S., Gaucher J., Kinouchi K., Kojima R., Gratton E., Li W., Baldi P., Imhof A., Okamura H., Sassone-Corsi P.

Science Advances （Science Advances） 6 （ 51 ） 2020年12月

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

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Reshaping circadian metabolism in the suprachiasmatic nucleus and prefrontal cortex by nutritional challenge

Tognini P., Samad M., Kinouchi K., Liu Y., Helbling J.C., Moisan M.P., Eckel-Mahan K.L., Baldi P., Sassone-Corsi P.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America） 117 （ 47 ） 29904 - 29913 2020年11月

ISSN 00278424

Food is a powerful entrainment cue for circadian clocks in peripheral tissues, and changes in the composition of nutrients have been demonstrated to metabolically reprogram peripheral clocks. However, how food challenges may influence circadian metabolism of the master clock in the suprachiasmatic nucleus (SCN) or in other brain areas is poorly understood. Using high-throughput metabolomics, we studied the circadian metabolome profiles of the SCN and medial prefrontal cortex (mPFC) in lean mice compared with mice challenged with a high-fat diet (HFD). Both the mPFC and the SCN displayed a robust cyclic metabolism, with a strikingly high sensitivity to HFD perturbation in an area-specific manner. The phase and amplitude of oscillations were drastically different between the SCN and mPFC, and the metabolic pathways impacted by HFD were remarkably region-dependent. Furthermore, HFD induced a significant increase in the number of cycling metabolites exclusively in the SCN, revealing an unsuspected susceptibility of the master clock to food stress.

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Metabolic rivalry: circadian homeostasis and tumorigenesis

Kinouchi K., Sassone-Corsi P.

Nature Reviews Cancer （Nature Reviews Cancer） 20 （ 11 ） 645 - 661 2020年11月

ISSN 1474175X

Circadian rhythms govern a large array of physiological and metabolic functions. Perturbations of the daily cycle have been linked to elevated risk of developing cancer as well as poor prognosis in patients with cancer. Also, expression of core clock genes or proteins is remarkably attenuated particularly in tumours of a higher stage or that are more aggressive, possibly linking the circadian clock to cellular differentiation. Emerging evidence indicates that metabolic control by the circadian clock underpins specific hallmarks of cancer metabolism. Indeed, to support cell proliferation and biomass production, the clock may direct metabolic processes of cancer cells in concert with non-clock transcription factors to control how nutrients and metabolites are utilized in a time-specific manner. We hypothesize that the metabolic switch between differentiation or stemness of cancer may be coupled to the molecular clockwork. Moreover, circadian rhythms of host organisms appear to dictate tumour growth and proliferation. This Review outlines recent discoveries of the interplay between circadian rhythms, proliferative metabolism and cancer, highlighting potential opportunities in the development of future therapeutic strategies.

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Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake

Gaucher J., Kinouchi K., Ceglia N., Montellier E., Peleg S., Greco C.M., Schmidt A., Forne I., Masri S., Baldi P., Imhof A., Sassone-Corsi P.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America） 116 （ 50 ） 25250 - 25259 2019年12月

ISSN 00278424

Binge drinking and chronic exposure to ethanol contribute to alcoholic liver diseases (ALDs). A potential link between ALDs and circadian disruption has been observed, though how different patterns of alcohol consumption differentially impact hepatic circadian metabolism remains virtually unexplored. Using acute versus chronic ethanol feeding, we reveal differential reprogramming of the circadian transcriptome in the liver. Specifically, rewiring of diurnal SREBP transcriptional pathway leads to distinct hepatic signatures in acetyl- CoA metabolism that are translated into the subcellular patterns of protein acetylation. Thus, distinct drinking patterns of alcohol dictate differential adaptation of hepatic circadian metabolism.

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(Pro)renin receptor accelerates development of sarcopenia via activation of Wnt/YAP signaling axis

Yoshida N., Endo J., Kinouchi K., Kitakata H., Moriyama H., Kataoka M., Yamamoto T., Shirakawa K., Morimoto S., Nishiyama A., Hashiguchi A., Higuchi I., Fukuda K., Ichihara A., Sano M.

Aging Cell （Aging Cell） 18 （ 5 ） 2019年10月

ISSN 14749718

To extend life expectancy and ensure healthy aging, it is crucial to prevent and minimize age-induced skeletal muscle atrophy, also known as sarcopenia. However, the disease's molecular mechanism remains unclear. The age-related Wnt/β-catenin signaling pathway has been recently shown to be activated by the (pro)renin receptor ((P)RR). We report here that (P)RR expression was increased in the atrophied skeletal muscles of aged mice and humans. Therefore, we developed a gain-of-function model of age-related sarcopenia via transgenic expression of (P)RR under control of the CAG promoter. Consistent with our hypothesis, (P)RR-Tg mice died early and exhibited muscle atrophy with histological features of sarcopenia. Moreover, Wnt/β-catenin signaling was activated and the regenerative capacity of muscle progenitor cells after cardiotoxin injury was impaired due to cell fusion failure in (P)RR-Tg mice. In vitro forced expression of (P)RR protein in C2C12 myoblast cells suppressed myotube formation by activating Wnt/β-catenin signaling. Administration of Dickkopf-related protein 1, an inhibitor of Wnt/β-catenin signaling, and anti-(P)RR neutralizing antibody, which inhibits binding of (P)RR to the Wnt receptor, significantly improved sarcopenia in (P)RR-Tg mice. Furthermore, the use of anti-(P)RR neutralizing antibodies significantly improved the regenerative ability of skeletal muscle in aged mice. Finally, we show that Yes-associated protein (YAP) signaling, which is coordinately regulated by Wnt/β-catenin, contributed to the development of (P)RR-induced sarcopenia. The present study demonstrates the use of (P)RR-Tg mice as a novel sarcopenia model, and shows that (P)RR-Wnt-YAP signaling plays a pivotal role in the pathogenesis of this disease.

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Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock

Pastore N., Vainshtein A., Herz N.J., Huynh T., Brunetti L., Klisch T.J., Mutarelli M., Annunziata P., Kinouchi K., Brunetti-Pierri N., Sassone-Corsi P., Ballabio A.

EMBO Journal （EMBO Journal） 38 （ 12 ） 2019年06月

ISSN 02614189

Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient-sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24-h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the diurnal cycle and altered gene expression causing abnormal circadian wheel-running behavior. In addition, TFEB and TFE3 directly regulate the expression of Rev-erbα (Nr1d1), a transcriptional repressor component of the core clock machinery also involved in the regulation of whole-body metabolism and autophagy. Comparative analysis of the cistromes of TFEB/TFE3 and REV-ERBα showed an extensive overlap of their binding sites, particularly in genes involved in autophagy and metabolic functions. These data reveal a direct link between nutrient and clock-dependent regulation of gene expression shedding a new light on the crosstalk between autophagy, metabolism, and circadian cycles.

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BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis

Welz P.S., Zinna V.M., Symeonidi A., Koronowski K.B., Kinouchi K., Smith J.G., Guillén I.M., Castellanos A., Crainiciuc G., Prats N., Caballero J.M., Hidalgo A., Sassone-Corsi P., Benitah S.A.

Cell （Cell） 177 （ 6 ） 1436 - 1447.e12 2019年05月

ISSN 00928674

Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to “remember” time in the absence of external cues. Light can synchronize circadian clocks within the epidermis in the absence of BMAL1-driven clocks in all other tissues.

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Defining the Independence of the Liver Circadian Clock

Koronowski K.B., Kinouchi K., Welz P.S., Smith J.G., Zinna V.M., Shi J., Samad M., Chen S., Magnan C.N., Kinchen J.M., Li W., Baldi P., Benitah S.A., Sassone-Corsi P.

Cell （Cell） 177 （ 6 ） 1448 - 1462.e14 2019年05月

ISSN 00928674

Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function. A autonomous branch of the liver circadian clock is independent from all other clocks yet still dependent on the light-dark cycle.

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Light Entrains Diurnal Changes in Insulin Sensitivity of Skeletal Muscle via Ventromedial Hypothalamic Neurons

Aras E., Ramadori G., Kinouchi K., Liu Y., Ioris R.M., Brenachot X., Ljubicic S., Veyrat-Durebex C., Mannucci S., Galié M., Baldi P., Sassone-Corsi P., Coppari R.

Cell Reports （Cell Reports） 27 （ 8 ） 2385 - 2398.e3 2019年05月

Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet the brain and peripheral pathways linking proper insulin effect to diurnal changes in light-dark and feeding-fasting inputs are poorly understood. Here, we show that the insulin sensitivity of several metabolically relevant tissues fluctuates during the 24 h period. For example, in mice, the insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function. Aras et al. provide in vivo evidence that tissue responsiveness to insulin varies in a diurnal fashion. In skeletal muscle, the authors show that photic inputs entrain diurnal changes in clock genes expression and insulin sensitivity via SIRT1 in neurons within the hypothalamic ventromedial nucleus.

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Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle

Kinouchi K., Magnan C., Ceglia N., Liu Y., Cervantes M., Pastore N., Huynh T., Ballabio A., Baldi P., Masri S., Sassone-Corsi P.

Cell Reports （Cell Reports） 25 （ 12 ） 3299 - 3314.e6 2018年12月

The circadian clock operates as intrinsic time-keeping machinery to preserve homeostasis in response to the changing environment. While food is a known zeitgeber for clocks in peripheral tissues, it remains unclear how lack of food influences clock function. We demonstrate that the transcriptional response to fasting operates through molecular mechanisms that are distinct from time-restricted feeding regimens. First, fasting affects core clock genes and proteins, resulting in blunted rhythmicity of BMAL1 and REV-ERBα both in liver and skeletal muscle. Second, fasting induces a switch in temporal gene expression through dedicated fasting-sensitive transcription factors such as GR, CREB, FOXO, TFEB, and PPARs. Third, the rhythmic genomic response to fasting is sustainable by prolonged fasting and reversible by refeeding. Thus, fasting imposes specialized dynamics of transcriptional coordination between the clock and nutrient-sensitive pathways, thereby achieving a switch to fasting-specific temporal gene regulation.

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Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks

Dyar K.A., Lutter D., Artati A., Ceglia N.J., Liu Y., Armenta D., Jastroch M., Schneider S., de Mateo S., Cervantes M., Abbondante S., Tognini P., Orozco-Solis R., Kinouchi K., Wang C., Swerdloff R., Nadeef S., Masri S., Magistretti P., Orlando V., Borrelli E., Uhlenhaut N.H., Baldi P., Adamski J., Tschöp M.H., Eckel-Mahan K., Sassone-Corsi P.

Cell （Cell） 174 （ 6 ） 1571 - 1585.e11 2018年09月

ISSN 00928674

Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease. Circadian metabolite profiles of eight different tissues under standard and high-fat diet uncover highly specialized communication and coherence among tissue clocks and how this is rewired by nutrient challenge.

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木内 謙一郎

論文 - 木内 謙一郎

木内　謙一郎

論文 - 木内　謙一郎