Faculty Profiles - YOSHIMURA, Takashi

Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261 Open Access

Masakazu Nambo, Taeko Nishiwaki-Ohkawa, Akihiro Ito, Zachary T. Ariki, Yuka Ito, Yuuki Kato, Muhammad Yar, Jacky C. -H. Yim, Emily Kim, Elizabeth Sharkey, Keiko Kano, Emi Mishiro-Sato, Kosuke Okimura, Michiyo Maruyama, Wataru Ota, Yuko Furukawa, Tomoya Nakayama, Misato Kobayashi, Fumihiko Horio, Ayato Sato, Cathleen M. Crudden, Takashi Yoshimura

Communications Medicine Vol. 4 ( 1 ) 2024.8

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide.

Methods

We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated.

Results

ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T<sub>3</sub>, a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1.

Conclusions

ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism.

DOI： 10.1038/s43856-024-00574-z

Other Link： https://www.nature.com/articles/s43856-024-00574-z

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179 Reviewed Open Access

Helmut Grasberger, Alexandra M. Dumitrescu, Xiao-Hui Liao, Elliott G. Swanson, Roy E. Weiss, Panudda Srichomkwun, Theodora Pappa, Junfeng Chen, Takashi Yoshimura, Phillip Hoffmann, Monica Malheiros França, Rebecca Tagett, Kazumichi Onigata, Sabine Costagliola, Jane Ranchalis, Mitchell R. Vollger, Andrew B. Stergachis, Jessica X. Chong, Michael J. Bamshad, Guillaume Smits, Gilbert Vassart, Samuel Refetoff

Nature Genetics Vol. 56 ( 5 ) page： 877 - 888 2024.5

FcRY is a key molecule controlling maternal blook IgY transfer to yolks during egg development in avian species Reviewed Open Access

Okamoto M, Sasaki R, Ikeda K, Doi K, Tatsumi F, Oshima K, Kojima T, Mizushima S, Ikegami K, Yoshimura T, Furukawa K, Kobayashi M, Horio F, Murai A

Frontiers in Immunology Vol. 15 page： 1305587 2024

A transcriptional program underlying the circannual rhythms of gonadal development in medaka Open Access

Tomoya Nakayama, Miki Tanikawa, Yuki Okushi, Thoma Itoh, Tsuyoshi Shimmura, Michiyo Maruyama, Taiki Yamaguchi, Akiko Matsumiya, Ai Shinomiya, Ying-Jey Guh, Junfeng Chen, Kiyoshi Naruse, Hiroshi Kudoh, Yohei Kondo, Honda Naoki, Kazuhiro Aoki, Atsushi J. Nagano, Takashi Yoshimura

Proceedings of the National Academy of Sciences Vol. 120 ( 52 ) 2023.12

Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences

To cope with seasonal environmental changes, organisms have evolved approximately 1-y endogenous circannual clocks. These circannual clocks regulate various physiological properties and behaviors such as reproduction, hibernation, migration, and molting, thus providing organisms with adaptive advantages. Although several hypotheses have been proposed, the genes that regulate circannual rhythms and the underlying mechanisms controlling long-term circannual clocks remain unknown in any organism. Here, we show a transcriptional program underlying the circannual clock in medaka fish ( Oryzias latipes ). We monitored the seasonal reproductive rhythms of medaka kept under natural outdoor conditions for 2 y. Linear regression analysis suggested that seasonal changes in reproductive activity were predominantly determined by an endogenous program. Medaka hypothalamic and pituitary transcriptomes were obtained monthly over 2 y and daily on all equinoxes and solstices. Analysis identified 3,341 seasonally oscillating genes and 1,381 daily oscillating genes. We then examined the existence of circannual rhythms in medaka via maintaining them under constant photoperiodic conditions. Medaka exhibited approximately 6-mo free-running circannual rhythms under constant conditions, and monthly transcriptomes under constant conditions identified 518 circannual genes. Gene ontology analysis of circannual genes highlighted the enrichment of genes related to cell proliferation and differentiation. Altogether, our findings support the “histogenesis hypothesis” that postulates the involvement of tissue remodeling in circannual time-keeping.

DOI： 10.1073/pnas.2313514120

Variation in responses to photoperiods and temperatures in Japanese medaka from different latitudes Open Access

Shinomiya A., Adachi D., Shimmura T., Tanikawa M., Hiramatsu N., Ijiri S., Naruse K., Sakaizumi M., Yoshimura T.

Zoological Letters Vol. 9 ( 1 ) 2023.12

Publisher：Zoological Letters

Seasonal changes are more robust and dynamic at higher latitudes than at lower latitudes, and animals sense seasonal changes in the environment and alter their physiology and behavior to better adapt to harsh winter conditions. However, the genetic basis for sensing seasonal changes, including the photoperiod and temperature, remains unclear. Medaka (Oryzias latipes species complex), widely distributed from subtropical to cool-temperate regions throughout the Japanese archipelago, provides an excellent model to tackle this subject. In this study, we examined the critical photoperiods and critical temperatures required for seasonal gonadal development in female medaka from local populations at various latitudes. Intraspecific differences in critical photoperiods and temperatures were detected, demonstrating that these differences were genetically controlled. Most medaka populations could perceive the difference between photoperiods for at least 1 h. Populations in the Northern Japanese group required 14 h of light in a 24 h photoperiod to develop their ovaries, whereas ovaries from the Southern Japanese group developed under 13 h of light. Additionally, Miyazaki and Ginoza populations from lower latitudes were able to spawn under short-day conditions of 11 and 10 h of light, respectively. Investigation of the critical temperature demonstrated that the Higashidori population, the population from the northernmost region of medaka habitats, had a critical temperature of over 18 °C, which was the highest critical temperature among the populations examined. The Miyazaki and the Ginoza populations, in contrast, were found to have critical temperatures under 14 °C. When we conducted a transplant experiment in a high-latitudinal environment using medaka populations with different seasonal responses, the population from higher latitudes, which had a longer critical photoperiod and a higher critical temperature, showed a slower reproductive onset but quickly reached a peak of ovarian size. The current findings show that low latitudinal populations are less responsive to photoperiodic and temperature changes, implying that variations in this responsiveness can alter seasonal timing of reproduction and change fitness to natural environments with varying harshnesses of seasonal changes. Local medaka populations will contribute to elucidating the genetic basis of seasonal time perception and adaptation to environmental changes.

DOI： 10.1186/s40851-023-00215-8

Orphan nuclear receptor nr4a1 regulates winter depression-like behavior in medaka Open Access

Nakayama T., Hirano F., Okushi Y., Matsuura K., Ohashi M., Matsumiya A., Yoshimura T.

Neuroscience Letters Vol. 814 2023.9

Publisher：Neuroscience Letters

About 10% of the population suffers from depression in winter at high latitude. Although it has become a serious public health issue, its underlying mechanism remains unknown and new treatments and therapies are required. As an adaptive strategy, many animals also exhibit depression-like behavior in winter. Previously, it has been reported that celastrol, a traditional Chinese medicine, can rescue winter depression-like behavior in medaka, an excellent model of winter depression. Nuclear receptor subfamily 4 group A member 1 (nr4a1, also known as nur77) is a known target of celastrol, and the signaling pathway of nr4a1 was suggested to be inactive in medaka brain during winter, implying the association of nr4a1 and winter depression-like behavior. However, the direct evidence for its involvement in winter depression-like behavior remains unclear. The present study found that nr4a1 was suppressed in the medaka brain under winter conditions. Cytosporone B, nr4a1 chemical activator, reversed winter depression-like behavior under winter conditions. Additionally, nr4a1 mutant fish generated by CRISPR/Cas9 system showed decreased sociability under summer conditions. Therefore, our results demonstrate that the seasonal regulation of nr4a1 regulates winter depression-like behavior and offers potential therapeutic target.

DOI： 10.1016/j.neulet.2023.137469

Novel hypnotics of Japanese traditional herbal medicines to caffeine-induced insomnia in Drosophila by using Newly-developed automated sleep and rhythm analysis system (AutoCircaS) Reviewed

Mimicking seasonal changes in light-dark cycle and ambient temperature modulates gut microbiome in mice under the same dietary regimen Reviewed

Matsumoto S, Ren L, Iigo M, Murai A, Yoshimura T

PLoS One Vol. 18 page： e0278013 2023.2

Inoue E, Suzuki T, Nakayama T, Yoshimura T, Sudo K, Shimizu Y, Iwaki Y, Kawasaki H, Ishida N

Gene Vol. 846 page： 146852 2022.12

Real time monitoring of cold Ca2+ dependent transcription and its modulation by NCX inhibitors Reviewed Open Access

Wang HT, Miyairi S, Kitamura M, Iizuka K, AsanoY, Yoshimura T, Kon N

Scientific Reports Vol. 12 ( 1 ) page： 17325 2022.12

Level of constitutively expressed BMAL1 affects the robustness of circadian oscillations Open Access

Padlom A., Ono D., Hamashima R., Furukawa Y., Yoshimura T., Nishiwaki-Ohkawa T.

Scientific Reports Vol. 12 ( 1 ) 2022.12

Publisher：Scientific Reports

The circadian rhythm is a biological oscillation of physiological activities with a period of approximately 24 h, that is driven by a cell-autonomous oscillator called the circadian clock. The current model of the mammalian circadian clock is based on a transcriptional-translational negative feedback loop in which the protein products of clock genes accumulate in a circadian manner and repress their own transcription. However, several studies have revealed that constitutively expressed clock genes can maintain circadian oscillations. To understand the underlying mechanism, we expressed Bmal1 in Bmal1-disrupted cells using a doxycycline-inducible promoter and monitored Bmal1 and Per2 promoter activity using luciferase reporters. Although the levels of BMAL1 and other clock proteins, REV-ERBα and CLOCK, showed no obvious rhythmicity, robust circadian oscillation in Bmal1 and Per2 promoter activities with the correct phase relationship was observed, which proceeded in a doxycycline-concentration-dependent manner. We applied transient response analysis to the Bmal1 promoter activity in the presence of various doxycycline concentrations. Based on the obtained transfer functions, we suggest that, at least in our experimental system, BMAL1 is not directly involved in the oscillatory process, but modulates the oscillation robustness by regulating basal clock gene promoter activity.

DOI： 10.1038/s41598-022-24188-4

Prostaglandin E2 synchronizes lunar-regulated beach spawning in grass puffers Reviewed Open Access

Junfeng Chen, Yuma Katada, Kousuke Okimura, Taiki Yamaguchi, Ying-Jey Guh, Tomoya Nakayama, Michiyo Maruyama, Yuko Furukawa, Yusuke Nakane, Naoyuki Yamamoto, Yoshikatsu Sato, Hironori Ando, Asako Sugimura, Kazufumi Tabata, Ayato Sato, Takashi Yoshimura

Current Biology Vol. 32 ( 22 ) page： 4881 - 4889.e5 2022.10

Adenylate kinase 1 overexpression increases locomotor activity in medaka fish Reviewed Open Access

Maruyama M, Furukawa Y, Kinoshita M, Mukaiyama A, Akiyama S, Yoshimura T

PLOS ONE Vol. 17 ( 1 January ) page： e0257967 2022.1

Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine. Reviewed International journal Open Access

Manhui Zhang, Kohei Kobayashi, Haruki Atsumi, Yuma Katada, Yusuke Nakane, Junfeng Chen, Ryo Nagano, Naoya Kadofusa, Taeko Nishiwaki-Ohkawa, Naohiro Kon, Tsuyoshi Hirota, Ayato Sato, Toshiaki Makino, Takashi Yoshimura

Scientific reports Vol. 11 ( 1 ) page： 21038 - 21038 2021.10

Language：English Publishing type：Research paper (scientific journal)

Circadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, cardiovascular disease, and cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target AKT and its relevant signaling pathways. As expected, analysis of the major ingredients targeting AKT signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of AKT, and triple knockdown of AKT isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption.

DOI： 10.1038/s41598-021-00499-w

Effects of Cryptochrome-modulating compounds on circadian behavioral rhythms in zebrafish. Reviewed International journal

Mui Iida, Yusuke Nakane, Takashi Yoshimura, Tsuyoshi Hirota

Journal of biochemistry Vol. 171 ( 5 ) page： 501 - 507 2021.9

Language：English Publishing type：Research paper (scientific journal)

The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101, and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins Cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioral rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.

DOI： 10.1093/jb/mvab096

ケミカルゲノミクスで明らかにするメダカの冬季うつ様行動の分子基盤：冬季うつ病の理解と克服にむけて Invited

沖村光祐，中山友哉，吉村崇

化学と生物 Vol. 59 page： 369 - 376 2021.8

Photoperiodic regulation of dopamine signaling regulates seasonal changes in retinal photosensitivity in mice. Reviewed International journal Open Access

Kousuke Okimura, Yusuke Nakane, Taeko Nishiwaki-Ohkawa, Takashi Yoshimura

Scientific reports Vol. 11 ( 1 ) page： 1843 - 1843 2021.1

Language：English Publishing type：Research paper (scientific journal)

At high latitudes, approximately 10% of people suffer from depression during the winter season, a phenomenon known as seasonal affective disorder (SAD). Shortened photoperiod and/or light intensity during winter season are risk factors for SAD, and bright light therapy is an effective treatment. Interestingly, reduced retinal photosensitivity along with the mood is observed in SAD patients in winter. However, the molecular basis underlying seasonal changes in retinal photosensitivity remains unclear, and pharmacological intervention is required. Here we show photoperiodic regulation of dopamine signaling and improvement of short day-attenuated photosensitivity by its pharmacological intervention in mice. Electroretinograms revealed dynamic seasonal changes in retinal photosensitivity. Transcriptome analysis identified short day-mediated suppression of the Th gene, which encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine biosynthesis. Furthermore, pharmacological intervention in dopamine signaling through activation of the cAMP signaling pathway rescued short day-attenuated photosensitivity, whereas dopamine receptor antagonists decreased photosensitivity under long-day conditions. Our results reveal molecular basis of seasonal changes in retinal photosensitivity in mammals. In addition, our findings provide important insights into the pathogenesis of SAD and offer potential therapeutic interventions.

DOI： 10.1038/s41598-021-81540-w

Light and Hormones in Seasonal Regulation of Reproduction and Mood Invited Reviewed

Chen Junfeng, Okimura Kousuke, Yoshimura Takashi

ENDOCRINOLOGY Vol. 161 ( 9 ) 2020.9

Publisher：Endocrinology (United States)

Organisms that inhabit the temperate zone exhibit various seasonal adaptive behaviors, including reproduction, hibernation, molting, and migration. Day length, known as photoperiod, is the most noise-free and widely used environmental cue that enables animals to anticipate the oncoming seasons and adapt their physiologies accordingly. Although less clear, some human traits also exhibit seasonality, such as birthrate, mood, cognitive brain responses, and various diseases. However, the molecular basis for human seasonality is poorly understood. Herein, we first review the underlying mechanisms of seasonal adaptive strategies of animals, including seasonal reproduction and stress responses during the breeding season. We then briefly summarize our recent discovery of signaling pathways involved in the winter depression-like phenotype in medaka fish. We believe that exploring the regulation of seasonal traits in animal models will provide insight into human seasonality and aid in the understanding of human diseases such as seasonal affective disorder (SAD).

DOI： 10.1210/endocr/bqaa130

Web of Science

Genetic analysis of body weight in wild populations of medaka fish from different latitudes. Reviewed International journal

Tamiris I Yassumoto, Mana Nakatsukasa, Atsushi J Nagano, Masaki Yasugi, Takashi Yoshimura, Ai Shinomiya

PloS one Vol. 15 ( 6 ) page： e0234803 2020.6

Language：English Publishing type：Research paper (scientific journal)

The genetic bases of growth and body weight are of economic and scientific interest, and teleost fish models have proven useful in such investigations. The Oryzias latipes species complex (medaka) is an abundant freshwater fish in Japan and suitable for genetic studies. We compared two wild medaka stocks originating from different latitudes. The Maizuru population from higher latitudes weighed more than the Ginoza population. We investigated the genetic basis of body weight, using quantitative trait locus (QTL) analysis of the F2 offspring of these populations. We detected one statistically significant QTL for body weight on medaka chromosome 4 and identified 12 candidate genes that might be associated with body weight or growth. Nine of these 12 genes had at least one single nucleotide polymorphism that caused amino acid substitutions in protein-coding regions, and we estimated the effects of these substitutions. The present findings might contribute to the marker-assisted selection of economically important aquaculture species.

DOI： 10.1371/journal.pone.0234803

Web of Science