masatomiyake/published_papers/52463421 Loc Dinh Nguyen Ly Huong Nguyen Dat Xuan Dao Tsuyoshi Hattori Mika Takarada-Iemata Hiroshi Ishii Takashi Tamatani Hiroshi Kawasaki Yohei Shinmyo Kenta Onoue Shigenobu Yonemura Jun Zhang Masato Miyake Seiichi Oyadomari Kazutoshi Mori Osamu Hori Impact of ATF6 deletion on the embryonic brain development. Although the unfolded protein response (UPR) is activated during brain development, its roles remain unclear. Here, we report that deletion of activating transcription factor 6 (ATF6), consisting of ATF6α and ATF6β, in the developing brain caused microcephaly and neonatal death in mice. Analysis of Atf6a/Atf6b double conditional knockout (dcKO) brains revealed diverse neuronal phenotypes, such as reduced neurogenesis, increased cell death, impaired cortical layer formation, and axon projection defects. Furthermore, hypervasculature, glial defects, and neuroinflammation were observed in dcKO brains. Notably, hypervasculature was detected at E14.5, when endoplasmic reticulum (ER) stress was morphologically unclear, but the UPR was activated to a greater extent in dcKO brains. Expression profiles revealed reduced levels of molecular chaperones in the ER and enhanced levels of PERK- and IRE1-downstream molecules, including VEGFA, in dcKO brains. Administration of a chemical chaperone 4-phenylbutyric acid partially rescued dcKO mice, suggesting roles of ATF6 for improving proteostasis and for coordinating the UPR. iScience 28 6 112569 112569 20250620 10.1016/j.isci.2025.112569 40487428 masatomiyake/published_papers/45784965 Jirapat Namkaew Jun Zhang Norio Yamakawa Yoshimasa Hamada Kazue Tsugawa Miho Oyadomari Masato Miyake Toyomasa Katagiri Seiichi Oyadomari Repositioning of mifepristone as an integrated stress response activator to potentiate cisplatin efficacy in non-small cell lung cancer. Lung cancer, primarily non-small-cell lung cancer (NSCLC), is a significant cause of cancer-related mortality worldwide. Cisplatin-based chemotherapy is a standard treatment for NSCLC; however, its effectiveness is often limited due to the development of resistance, leading to NSCLC recurrence. Thus, the identification of effective chemosensitizers for cisplatin is of paramount importance. The integrated stress response (ISR), activated by various cellular stresses and mediated by eIF2α kinases, has been implicated in drug sensitivity. ISR activation globally suppresses protein synthesis while selectively promoting the translation of ATF4 mRNA, which can induce pro-apoptotic proteins such as CHOP, ATF3, and TRIB3. To expedite and economize the development of chemosensitizers for cisplatin treatment in NSCLC, we employed a strategy to screen an FDA-approved drug library for ISR activators. In this study, we identified mifepristone as a potent ISR activator. Mifepristone activated the HRI/eIF2α/ATF4 axis, leading to the induction of pro-apoptotic factors, independent of its known role as a synthetic steroid. Our in vitro and in vivo models demonstrated mifepristone's potential to inhibit NSCLC re-proliferation following cisplatin treatment and tumor growth, respectively, via the ISR-mediated cell death pathway. These findings suggest that mifepristone, as an ISR activator, could enhance the efficacy of cisplatin-based therapy for NSCLC, highlighting the potential of drug repositioning in the search for effective chemosensitizers. Cancer letters 582 216509 216509 20240201 10.1016/j.canlet.2023.216509 38036042 masatomiyake/published_papers/43030121 Qiqiao Du Jieyu Wu Carina Fischer Takahiro Seki Xu Jing Juan Gao Xingkang He Kayoko Hosaka Le Tong Akihiro Yasue Masato Miyake Mitsuaki Sobajima Seiichi Oyadomari Xiaoting Sun Yunlong Yang Qinjun Zhou Minghua Ge Wei Tao Shuzhong Yao Yihai Cao Generation of mega brown adipose tissue in adults by controlling brown adipocyte differentiation in vivo. Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other β3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM). Proceedings of the National Academy of Sciences of the United States of America 119 40 e2203307119 null 20221004 10.1073/pnas.2203307119 36161914 masatomiyake/published_papers/37932431 Mitsuaki Sobajima Masato Miyake Yoshimasa Hamada Kazue Tsugawa Miho Oyadomari Ryota Inoue Jun Shirakawa Hiroshi Arima Seiichi Oyadomari The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion. Stress-inducible transcription factor ATF4 is essential for survival and identity of β-cell during stress conditions. However, the physiological role of ATF4 in β-cell function is not yet completely understood. To understand the role of ATF4 in glucose-stimulated insulin secretion (GSIS), β-cell-specific Atf4 knockout (βAtf4KO) mice were phenotypically characterized. Insulin secretion and mechanistic analyses were performed using islets from control Atf4f/f and βAtf4KO mice to assess key regulators for triggering and amplifying signals for GSIS. βAtf4KO mice displayed glucose intolerance due to reduced insulin secretion. Moreover, βAtf4KO islets exhibited a decrease in both the insulin content and first-phase insulin secretion. The analysis of βAtf4KO islets showed that ATF4 is required for insulin production and glucose-stimulated ATP and cAMP production. The results demonstrate that ATF4 contributes to the multifaceted regulatory process in GSIS even under stress-free conditions. Biochemical and biophysical research communications 611 165 171 20220416 10.1016/j.bbrc.2022.04.038 35489203 masatomiyake/published_papers/36990121 Masato Miyake Mitsuaki Sobajima Kiyoe Kurahashi Akira Shigenaga Masaya Denda Akira Otaka Tomohide Saio Naoki Sakane Hidetaka Kosako Seiichi Oyadomari Identification of an endoplasmic reticulum proteostasis modulator that enhances insulin production in pancreatic β cells Elsevier BV Cell Chemical Biology 2451-9456 29 6 996 1009.e9 20220200 10.1016/j.chembiol.2022.01.002 masatomiyake/published_papers/37646893 Masato Miyake Jun Zhang Akihiro Yasue Satoshi Hisanaga Kazue Tsugawa Hiroshi Sakaue Miho Oyadomari Hiroshi Kiyonari Seiichi Oyadomari Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity. The eIF2α phosphorylation-dependent integrated stress response (ISR) is a signaling pathway that maintains homeostasis in mammalian cells exposed to various stresses. Here, ISR activation in adipocytes improves obesity and diabetes by regulating appetite in a non-cell-autonomous manner. Adipocyte-specific ISR activation using transgenic mice decreases body weight and improves glucose tolerance and obesity induced by a high-fat diet (HFD) via preferential inhibition of HFD intake. The transcriptome analysis of ISR-activated adipose tissue reveals that growth differentiation factor 15 (GDF15) expression is induced by the ISR through the direct regulation of the transcription factors ATF4 and DDIT3. Deficiency in the GDF15 receptor GFRAL abolishes the adipocyte ISR-dependent preferential inhibition of HFD intake and the anti-obesity effects. Pharmacologically, 10(E), 12(Z)-octadecadienoic acid induces ISR-dependent GDF15 expression in adipocytes and decreases the intake of the HFD. Based on our findings the specific activation of the ISR in adipocytes controls the non-cell-autonomous regulation of appetite. iScience 24 12 103448 103448 20211217 10.1016/j.isci.2021.103448 34877504 masatomiyake/published_papers/35016033 Yu Saito Tetsuya Ikemoto Kazunori Tokuda Katsuki Miyazaki Shinichiro Yamada Satoru Imura Masato Miyake Yuji Morine Seiichi Oyadomari Mitsuo Shimada Effective three-dimensional culture of hepatocyte-like cells generated from human adipose-derived mesenchymal stem cells. BACKGROUND: The aim of this study was to clarify the effectiveness of a new three-dimensional (3D) culture system for hepatocyte-like cells (HLCs) generated from human adipose-derived mesenchymal stem cells (ADSCs). METHODS: Human ADSCs (2 × 104 ) with or without 0.1 mg/mL human recombinant peptide μ-piece per well were seeded in a 96-well U-bottom plate and then our three-step differentiation protocol was applied for 21 days. At each step, cell morphology and gene expression were investigated. Mature hepatocyte functions were evaluated after HLC differentiation. These parameters were compared between 2D- and 3D-cultured HLCs, and, DNA microarray analysis was also performed. Finally, HLCs were transplanted in to CCl4 induced acute liver failure model mice. RESULTS: Two-dimensional-cultured HLCs at day 21 did not have a spindle shape and had formed spheroids after day 6, which gradually increased in size for 3D-cultured HLCs. Definitive endoderm, hepatoblast, and hepatocyte genes showed significantly higher expression in the 3D culture group. Three-dimensional-cultured HLCs also had higher albumin expression, CYP3A4 activity, urea synthesis, and ammonium metabolism, and much higher expression of ion transporter, blood coagulation, and cell communication genes. HLC transplantation improved serum liver function, especially in T-Bil levels, and engrafted into immunodeficient mice with HLA class I positive staining. CONCLUSION: Our new 3D culture protocol is effective to improve hepatocyte functions. Our HLCs might be promising for clinical cell transplantation to treat metabolic disease. Journal of hepato-biliary-pancreatic sciences 28 9 705 715 20210728 10.1002/jhbp.1024 34318615 masatomiyake/published_papers/35157605 Dinh Thi Nguyen Thuong Manh Le Tsuyoshi Hattori Mika Takarada-Iemata Hiroshi Ishii Jureepon Roboon Takashi Tamatani Takayuki Kannon Kazuyoshi Hosomichi Atsushi Tajima Shusuke Taniuchi Masato Miyake Seiichi Oyadomari Takashi Tanaka Nobuo Kato Shunsuke Saito Kazutoshi Mori Osamu Hori The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity. While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b-/- mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b-/- neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b-/- and Calr+/- mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis. Scientific reports 11 1 13086 13086 20210622 10.1038/s41598-021-92529-w 34158584 masatomiyake/published_papers/31975112 Hironori Kato Kohki Okabe Masato Miyake Kazuki Hattori Tomohiro Fukaya Kousuke Tanimoto Shi Beini Mariko Mizuguchi Satoru Torii Satoko Arakawa Masaya Ono Yusuke Saito Takashi Sugiyama Takashi Funatsu Katsuaki Sato Shigeomi Shimizu Seiichi Oyadomari Hidenori Ichijo Hisae Kadowaki Hideki Nishitoh ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. Mitochondria play a central role in the function of brown adipocytes (BAs). Although mitochondrial biogenesis, which is indispensable for thermogenesis, is regulated by coordination between nuclear DNA transcription and mitochondrial DNA transcription, the molecular mechanisms of mitochondrial development during BA differentiation are largely unknown. Here, we show the importance of the ER-resident sensor PKR-like ER kinase (PERK) in the mitochondrial thermogenesis of brown adipose tissue. During BA differentiation, PERK is physiologically phosphorylated independently of the ER stress. This PERK phosphorylation induces transcriptional activation by GA-binding protein transcription factor α subunit (GABPα), which is required for mitochondrial inner membrane protein biogenesis, and this novel role of PERK is involved in maintaining the body temperatures of mice during cold exposure. Our findings demonstrate that mitochondrial development regulated by the PERK-GABPα axis is indispensable for thermogenesis in brown adipose tissue. Life science alliance 3 3 null null 20200300 10.26508/lsa.201900576 32029570 masatomiyake/published_papers/31975111 Yoshimasa Hamada Yuji Furumoto Akira Izutani Shusuke Taniuchi Masato Miyake Miho Oyadomari Kenji Teranishi Naoyuki Shimomura Seiichi Oyadomari Nanosecond pulsed electric fields induce the integrated stress response via reactive oxygen species-mediated heme-regulated inhibitor (HRI) activation. The integrated stress response (ISR) is one of the most important cytoprotective mechanisms and is integrated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Four eIF2α kinases, heme-regulated inhibitor (HRI), double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2), are activated in response to several stress conditions. We previously reported that nanosecond pulsed electric fields (nsPEFs) are a potential therapeutic tool for ISR activation. In this study, we examined which eIF2α kinase is activated by nsPEF treatment. To assess the responsible eIF2α kinase, we used previously established eIF2α kinase quadruple knockout (4KO) and single eIF2α kinase-rescued 4KO mouse embryonic fibroblast (MEF) cells. nsPEFs 70 ns in duration with 30 kV/cm electric fields caused eIF2α phosphorylation in wild-type (WT) MEF cells. On the other hand, nsPEF-induced eIF2α phosphorylation was completely abolished in 4KO MEF cells and was recovered by HRI overexpression. CM-H2DCFDA staining showed that nsPEFs generated reactive oxygen species (ROS), which activated HRI. nsPEF-induced eIF2α phosphorylation was blocked by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). Our results indicate that the eIF2α kinase HRI is responsible for nsPEF-induced ISR activation and is activated by nsPEF-generated ROS. PloS one 15 3 e0229948 null 20200000 10.1371/journal.pone.0229948 32155190 masatomiyake/published_papers/31975113 Keisuke Kitakaze Shusuke Taniuchi Eri Kawano Yoshimasa Hamada Masato Miyake Miho Oyadomari Hirotatsu Kojima Hidetaka Kosako Tomoko Kuribara Suguru Yoshida Takamitsu Hosoya Seiichi Oyadomari Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity. The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress. eLife 8 null null 20191217 10.7554/eLife.43302 31843052 masatomiyake/published_papers/31975114 Satoshi Hisanaga Masato Miyake Shusuke Taniuchi Miho Oyadomari Masatoshi Morimoto Ryosuke Sato Jun Hirose Hiroshi Mizuta Seiichi Oyadomari PERK-mediated translational control is required for collagen secretion in chondrocytes. As chondrocytes are highly secretory and they experience a variety of stresses, physiological unfolded protein response (UPR) signalling is essential for extracellular matrix (ECM) secretion and chondrogenesis. In the three branches of the UPR pathway, PERK governs the translational attenuation and transcriptional upregulation of amino acid and redox metabolism and induction of apoptosis. It was previously demonstrated that a defect of the PERK branch of the UPR signalling pathway causes the accumulation of unfolded proteins, leading to cell death without perturbing endoplasmic reticulum (ER)-to-Golgi transport in pancreatic β cells. However, little is known about the role of PERK in chondrocytes. In this study, we found that PERK signalling is activated in chondrocytes, and inhibition of PERK reduces collagen secretion despite causing excessive collagen synthesis in the ER. Perk -/- mice displayed reduced collagen in articular cartilage but no differences in chondrocyte proliferation or apoptosis compared to the findings in wild-type mice. PERK inhibition increases misfolded protein levels in the ER, which largely hinder ER-to-Golgi transport. These results suggest that the translational control mediated by PERK is a critical determinant of ECM secretion in chondrocytes. Scientific reports 8 1 773 773 20180115 10.1038/s41598-017-19052-9 29335505 masatomiyake/published_papers/31975115 Carina Fischer Takahiro Seki Sharon Lim Masaki Nakamura Patrik Andersson Yunlong Yang Jennifer Honek Yangang Wang Yanyan Gao Fang Chen Nilesh J Samani Jun Zhang Masato Miyake Seiichi Oyadomari Akihiro Yasue Xuri Li Yun Zhang Yizhi Liu Yihai Cao A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning. Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327-FGF10-FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases. Nature communications 8 1 2079 2079 20171212 10.1038/s41467-017-02158-z 29233981 masatomiyake/published_papers/31975117 Kiyoe Kurahashi Seika Inoue Sumiko Yoshida Yasumasa Ikeda Kana Morimoto Ryoko Uemoto Kazue Ishikawa Takeshi Kondo Tomoyuki Yuasa Itsuro Endo Masato Miyake Seiichi Oyadomari Toshio Matsumoto Masahiro Abe Hiroshi Sakaue Ken-Ichi Aihara The Role of Heparin Cofactor Ⅱ in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice. AIM: Accelerated thrombin action is associated with insulin resistance. It is known that upon activation by binding to dermatan sulfate proteoglycans, heparin cofactor Ⅱ(HCⅡ) inactivates thrombin in tissues. Because HCⅡ may be involved in glucose metabolism, we investigated the relationship between plasma HCⅡ activity and insulin resistance. METHODS AND RESULTS: In a clinical study, statistical analysis was performed to examine the relationships between plasma HCⅡ activity, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR) in elderly Japanese individuals with lifestyle-related diseases. Multiple regression analysis showed significant inverse relationships between plasma HCⅡ activity and HbA1c (p=0.014), FPG (p=0.007), and HOMA-IR (p= 0.041) in elderly Japanese subjects. In an animal study, HCⅡ+/+ mice and HCⅡ+/- mice were fed with a normal diet or high-fat diet (HFD) until 25 weeks of age. HFD-fed HCⅡ+/- mice exhibited larger adipocyte size, higher FPG level, hyperinsulinemia, compared to HFD-fed HCⅡ+/+ mice. In addition, HFD-fed HCⅡ+/- mice exhibited augmented expression of monocyte chemoattractant protein-1 and tumor necrosis factor, and impaired phosphorylation of the serine/threonine kinase Akt and AMP-activated protein kinase in adipose tissue compared to HFD-fed HCⅡ+/+ mice. The expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was also enhanced in the hepatic tissues of HFD-fed HCⅡ+/- mice. CONCLUSIONS: The present studies provide evidence to support the idea that HCⅡ plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HCⅡ production may serve as novel therapeutic tools for the treatment of type 2 diabetes. Journal of atherosclerosis and thrombosis 24 12 1215 1230 20171201 10.5551/jat.37739 28502917 masatomiyake/published_papers/31975116 Masato Miyake Masashi Kuroda Hiroshi Kiyonari Kenji Takehana Satoshi Hisanaga Masatoshi Morimoto Jun Zhang Miho Oyadomari Hiroshi Sakaue Seiichi Oyadomari Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice. BACKGROUND: Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly. OBJECTIVE: The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. MATERIAL AND METHODS: A ligand-activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2α (eIF2α), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle α-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice. RESULTS: HSA-Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2α in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice. CONCLUSIONS: As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics. PloS one 12 6 e0179955 null 20170000 10.1371/journal.pone.0179955 28644884 masatomiyake/published_papers/31975118 Shusuke Taniuchi Masato Miyake Kazue Tsugawa Miho Oyadomari Seiichi Oyadomari Integrated stress response of vertebrates is regulated by four eIF2α kinases. The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively. Because eIF2α is phosphorylated under various stress conditions, the existence of an additional eIF2α kinase has been suggested. To validate the existence of the unidentified eIF2α kinase, we constructed an eIF2α kinase quadruple knockout cells (4KO cells) in which the four known eIF2α kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2α was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2α kinases are sufficient for ISR and that there are no additional eIF2α kinases in vertebrates. Scientific reports 6 32886 32886 20160916 10.1038/srep32886 27633668 masatomiyake/published_papers/31975120 Masato Miyake Akitoshi Nomura Atsushi Ogura Kenji Takehana Yoshihiro Kitahara Kazuna Takahara Kazue Tsugawa Chinobu Miyamoto Naoko Miura Ryosuke Sato Kiyoe Kurahashi Heather P Harding Miho Oyadomari David Ron Seiichi Oyadomari Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism. The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 2 798 812 20160200 10.1096/fj.15-275990 26487695 masatomiyake/published_papers/31975119 Hitoshi Watanabe Tatsuya Nakano Ryo Saito Daisuke Akasaka Kazuki Saito Hideki Ogasawara Takeshi Minashima Kohtaro Miyazawa Takashi Kanaya Ikuro Takakura Nao Inoue Ikuo Ikeda Xiangning Chen Masato Miyake Haruki Kitazawa Hitoshi Shirakawa Kan Sato Kohji Tahara Yuya Nagasawa Michael T Rose Shyuichi Ohwada Kouichi Watanabe Hisashi Aso Serotonin Improves High Fat Diet Induced Obesity in Mice. There are two independent serotonin (5-HT) systems of organization: one in the central nervous system and the other in the periphery. 5-HT affects feeding behavior and obesity in the central nervous system. On the other hand, peripheral 5-HT also may play an important role in obesity, as it has been reported that 5-HT regulates glucose and lipid metabolism. Here we show that the intraperitoneal injection of 5-HT to mice inhibits weight gain, hyperglycemia and insulin resistance and completely prevented the enlargement of intra-abdominal adipocytes without having any effect on food intake when on a high fat diet, but not on a chow diet. 5-HT increased energy expenditure, O2 consumption and CO2 production. This novel metabolic effect of peripheral 5-HT is critically related to a shift in the profile of muscle fiber type from fast/glycolytic to slow/oxidative in soleus muscle. Additionally, 5-HT dramatically induced an increase in the mRNA expression of peroxisome proliferator-activated receptor coactivator 1α (PGC-1α)-b and PGC-1α-c in soleus muscle. The elevation of these gene mRNA expressions by 5-HT injection was inhibited by treatment with 5-HT receptor (5HTR) 2A or 7 antagonists. Our results demonstrate that peripheral 5-HT may play an important role in the relief of obesity and other metabolic disorders by accelerating energy consumption in skeletal muscle. PloS one 11 1 e0147143 null 20160000 10.1371/journal.pone.0147143 26766570 masatomiyake/published_papers/41476054 Hiroshi Fukuda Masato Miyake Hiroto Hirai Kenji Teranishi Naoyuki Shimomura Seiichi Oyadomari EFFECTS ON ENDOPLASMIC RETICULUM STRESS RESPONSE OF APPLYING NANOSECOND PULSED ELECTRIC FIELDS 2015 IEEE PULSED POWER CONFERENCE (PPC) null null 20150000 masatomiyake/published_papers/38462160 H. Takahashi K. Sato T. Yamaguchi M. Miyake H. Watanabe Y. Nagasawa E. Kitagawa S. Terada M. Urakawa M. T. Rose C. D. McMahon K. Watanabe S. Ohwada T. Gotoh H. Aso Myostatin alters glucose transporter-4 (GLUT4) expression in bovine skeletal muscles and myoblasts isolated from. double-muscled (DM) and normal-muscled (NM) Japanese Shorthorn cattle. DOMESTIC ANIMAL ENDOCRINOLOGY 1879-0054 48 62 68 20140700 10.1016/j.domaniend.2014.01.007 24906930 masatomiyake/published_papers/41476050 Hiroto Hirai Masato Miyake Akihiko Nagano Kenji Teranishi Naoyuki Shimomura Seiichi Oyadomari Investigation about Effects on Endoplasmic Reticulum Stress Responses by Applying Nanosecond Pulsed Electric Fields 2014 IEEE INTERNATIONAL POWER MODULATOR AND HIGH VOLTAGE CONFERENCE (IPMHVC) 2380-808X 419 422 20140000 masatomiyake/published_papers/31975122 Shunsuke Iwasaki Masato Miyake Hitoshi Watanabe Eri Kitagawa Kouichi Watanabe Shyuichi Ohwada Haruki Kitazawa Michael T Rose Hisashi Aso Expression of myostatin in neural cells of the olfactory system. Recent studies show that myostatin mRNA expression is found in some regions of the brain. However, the functional significance of this is currently unknown. We therefore investigated myostatin expression and function in the brain. In this study, we used immunohistochemistry, in situ hybridization, and RT-PCR analysis to reveal that myostatin is expressed in the mitral cells in the olfactory bulb (OB) and in neurons in the olfactory cortex (OC). Using 3D reconstruction, mitral cells positive for myostatin were positioned in the lateral and ventral regions of the OB. In contrast, myostatin-positive mitral cells were detected in mice at 2 weeks of age, but not on days 0 and 7 after birth. Activin receptor IIB, a myostatin receptor, was expressed in the OB, OC, hippocampus, and paraventricular thalamic nucleus. Moreover, c-Fos immunostaining in granule cells in the OB was augmented after intracerebroventricular injection of myostatin. These findings suggest that myostatin is localized in specific cells associated with the olfactory system of the brain and may act as a key inhibitor in cell and/or signal development of the olfactory system. Molecular neurobiology 47 1 1 8 20130200 10.1007/s12035-012-8342-1 22941030 masatomiyake/published_papers/31975121 Shunsuke Iwasaki Masato Miyake Shinichiro Hayashi Hitoshi Watanabe Yuya Nagasawa Shunsuke Terada Kouichi Watanabe Shyuichi Ohwada Haruki Kitazawa Michael T Rose Hisashi Aso Effect of myostatin on chemokine expression in regenerating skeletal muscle cells. Transforming growth factor-β (TGF-β) is implicated in the regulatory expression of chemokines that control multiple steps in myogenesis. However, it remains to be established whether myostatin, a member of the TGF-β superfamily, affects chemokine expression in skeletal muscle. We investigated the effects of myostatin on the expression of mRNAs and proteins for 4 chemokines (CXCL1, CXCL2, CXCL6, CCL2) in intact and regenerating musculus longissimus thoracis from normal-muscled (NM) and double-muscled (DM) cattle. These chemokines were expressed in regenerating muscle, and their expression was always lower in DM than in NM cattle. Immunohistochemistry revealed that CXCL1 and CXCL6 were detected in the regenerating areas of myoblasts and myotubes in both NM and DM cattle. In cultures of myoblasts isolated from the regenerating muscles, significantly less CXCL1, CXCL2 and CCL2 mRNA was expressed in DM myoblasts than in NM myoblasts during the proliferating stage (P-stage). The expression of CXCL1, CXCL2 and CCL2 mRNAs in NM myoblasts and CXCL1, CXCL2 and CXCL6 mRNAs in DM myoblasts decreased upon switching from P-stage to fusion stage (F-stage). Also, the expression of CXCL1, CXCL2 and CXCL6 mRNAs was significantly lower in DM than in NM myoblasts during the F-stage. The addition of 100 ng/ml myostatin during the F-stage attenuated the expression of CXCL1 and CXCL2 mRNAs and augmented that of CCL2. These results show for the first time that myostatin regulates the differential expression of chemokines in skeletal muscle cells. Cells, tissues, organs 198 1 66 74 20130000 10.1159/000351462 23838214 masatomiyake/published_papers/31975123 Masato Miyake Hideyuki Takahashi Eri Kitagawa Hitoshi Watanabe Takahiro Sakurada Hisashi Aso Takahiro Yamaguchi AMPK activation by AICAR inhibits myogenic differentiation and myostatin expression in cattle. AMP-activated protein kinase (AMPK) regulates metabolism in skeletal muscle, and myostatin (MSTN) negatively regulates skeletal muscle development and growth. In the present study, AMPK activation and the relationship between AMPK and MSTN during myogenic differentiation were investigated in cultures derived from bovine skeletal muscle. Myoblasts capable of forming myotubes were obtained from bovine skeletal muscle and treated with AICAR to activate AMPK, resulting in suppressed myotube formation. AICAR treatment significantly reduced the expression of MSTN mRNA during myogenic differentiation. Combined treatment with AICAR and MSTN suppressed myotube formation to a greater extent than AICAR alone. SB431542, an inhibitor of MSTN signaling, promoted myotube formation during myogenic differentiation. However, simultaneous treatment with AICAR blocked this effect of SB431542. Therefore, AMPK activation inhibits myogenic differentiation but may suppress MSTN expression to balance muscle development. Cell and tissue research 349 2 615 23 20120800 10.1007/s00441-012-1422-8 22622802 masatomiyake/published_papers/31975125 Masato Miyake Shinichiro Hayashi Shunsuke Iwasaki Takafumi Uchida Kouichi Watanabe Shyuichi Ohwada Hisashi Aso Takahiro Yamaguchi TIEG1 negatively controls the myoblast pool indispensable for fusion during myogenic differentiation of C2C12 cells. The transforming growth factor (TGF)-β inducible early gene (TIEG)-1 is implicated in the control of cell proliferation, differentiation, and apoptosis in some cell types. Since TIEG1 functioning may be associated with TGF-β, a suppressor of myogenesis, TIEG1 is also likely to be involved in myogenesis. Therefore, we investigated the function of TIEG1 during myogenic differentiation in vitro using the murine myoblasts cell line, C2C12. TIEG1 expression increased during differentiation of C2C12 cells. Constitutive expression of TIEG1 reduced survival and decreased myotube formation. Conversely, knocking down TIEG1 expression increased the number of viable cells during differentiation, and accelerated myoblast fusion into multinucleated myotubes. However, expression of the myogenic differentiation marker, myogenin, remained unaffected by TIEG1 knockdown. The mechanism underlying these events was investigated by focusing on the regulation of myoblast numbers after induction of differentiation. The knockdown of TIEG1 led to changes in cell cycle status and inhibition of apoptosis during the initial stages of differentiation. Microarray and real-time PCR analyses showed that the regulators of cell cycle progression were highly expressed in TIEG1 knockdown cells. Therefore, TIEG1 is a negative regulator of the myoblast pool that causes inhibition of myotube formation during myogenic differentiation. Journal of cellular physiology 226 4 1128 36 20110400 10.1002/jcp.22434 20945337 masatomiyake/published_papers/31975127 Hitoshi Watanabe Daisuke Akasaka Hideki Ogasawara Kan Sato Masato Miyake Kazuki Saito Yu Takahashi Takashi Kanaya Ikuro Takakura Tetsuya Hondo Guozheng Chao Michael T Rose Shyuichi Ohwada Kouichi Watanabe Takahiro Yamaguchi Hisashi Aso Peripheral serotonin enhances lipid metabolism by accelerating bile acid turnover. Serotonin is synthesized by two distinct tryptophan hydroxylases, one in the brain and one in the periphery. The latter is known to be unable to cross the blood-brain barrier. These two serotonin systems have apparently independent functions, although the functions of peripheral serotonin have yet to be fully elucidated. In this study, we have investigated the physiological effect of peripheral serotonin on the concentrations of metabolites in the circulation and in the liver. After fasting, mice were ip injected with 1 mg serotonin. The plasma glucose concentration was significantly elevated between 60 and 270 min after the injection. In contrast, plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations were decreased. The hepatic glycogen synthesis and concentrations were significantly higher at 240 min. At the same time, the hepatic triglyceride content was significantly lower than the basal levels noted before the serotonin injection, whereas the hepatic cholesterol content was significantly higher by 60 min after the injection. Furthermore, serotonin stimulated the contraction of the gallbladder and the excretion of bile. After the serotonin injection, there was a significant induction of apical sodium-dependent bile acid transporter expression, resulting in a decrease in the concentration of bile acids in the feces. Additionally, data are presented to show that the functions of serotonin are mediated through diverse serotonin receptor subtypes. These data indicate that peripheral serotonin accelerates the metabolism of lipid by increasing the concentration of bile acids in circulation. Endocrinology 151 10 4776 86 20101000 10.1210/en.2009-1349 20685881 masatomiyake/published_papers/31975130 Masato Miyake Shinichiro Hayashi Yoshikazu Taketa Shunsuke Iwasaki Kouichi Watanabe Shyuich Ohwada Hisashi Aso Takahiro Yamaguchi Myostatin down-regulates the IGF-2 expression via ALK-Smad signaling during myogenesis in cattle. Myostatin (MSTN) is a negative regulator during muscle differentiation, whereas insulin-like growth factors (IGFs) are essential for muscle development. MSTN and IGFs act oppositely during myogenesis, but there is little information on the mutual relationship of MSTN and IGFs. The present study was conducted to examine whether MSTN affects IGF expression during early myogenesis in cattle. IGF-1 mRNA was similarly expressed in M. longissimus thoracis of double-muscled (DM) and normal (NM) Japanese shorthorn cattle. IGF-2 mRNA expression was consistently higher in the normal and regenerating muscle of DM cattle than those of NM cattle. When myoblasts were isolated from regenerating M. longissimus thoracis, IGF-2 mRNA expression showed a significant increase in differentiating DM derived myoblasts (DM-myoblasts) as compared with differentiating NM derived myoblasts (NM-myoblasts). An addition of recombinant mouse myostatin (rMSTN) to myoblast cultures attenuated IGF-2 mRNA expression and decreased myotube formation, but did not effect IGF-1 mRNA expression. An activin-like kinase (ALK) inhibitor, SB431542, mediates MSTN action, suppressed the translocation of Smad2/3 into the nucleus in DM-myoblasts, and restored the attenuated IGF-2 mRNA expression and the decreased myotube formation induced by rMSTN in myoblast cultures. The findings indicate that MSTN may negatively regulate myoblast differentiation by suppressing IGF-2 expression via ALK-Smad signaling. Animal science journal = Nihon chikusan Gakkaiho 81 2 223 9 20100400 10.1111/j.1740-0929.2009.00725.x 20438504 masatomiyake/published_papers/31975132 Masato Miyake Shinichiro Hayashi Shunsuke Iwasaki Guozheng Chao Hideyuki Takahashi Kouichi Watanabe Shyuichi Ohwada Hisashi Aso Takahiro Yamaguchi Possible role of TIEG1 as a feedback regulator of myostatin and TGF-beta in myoblasts. Myostatin and TGF-beta negatively regulate skeletal muscle development and growth. Both factors signal through the Smad2/3 pathway. However, the regulatory mechanism of myostatin and TGF-beta signaling remains unclear. TGF-beta inducible early gene (TIEG) 1 is highly expressed in skeletal muscle and has been implicated in the modulation of TGF-beta signaling. These findings prompted us to investigate the effect of TIEG1 on myostatin and TGF-beta signaling using C2C12 myoblasts. Myostatin and TGF-beta induced the expression of TIEG1 and Smad7 mRNAs, but not TIEG2 mRNA, in proliferating C2C12 cells. When differentiating C2C12 myoblasts were stimulated by myostatin, TIEG1 mRNA was up-regulated at a late stage of differentiation. In contrast, TGF-beta enhanced TIEG1 expression at an early stage. Overexpression of TIEG1 prevented the transcriptional activation of Smad by myostatin and TGF-beta in both proliferating or differentiating C2C12 cells, but the expression of Smad2 and Smad7 mRNAs was not affected. Forced expression of TIEG1 inhibited myogenic differentiation but did not cause more inhibition than the empty vector in the presence of myostatin or TGF-beta. These results demonstrate that TIEG1 is one possible feedback regulator of myostatin and TGF-beta that prevents excess action in myoblasts. Biochemical and biophysical research communications 393 4 762 6 20100319 10.1016/j.bbrc.2010.02.077 20171187 masatomiyake/published_papers/31975134 Susumu Muroya Kouichi Watanabe Shinichiro Hayashi Masato Miyake Shigeru Konashi Youichi Sato Manabu Takahashi Shigeki Kawahata Yoshisato Yoshikawa Hisashi Aso Koichi Chikuni Takahiro Yamaguchi Muscle type-specific effect of myostatin deficiency on myogenic regulatory factor expression in adult double-muscled Japanese Shorthorn cattle. To clarify muscle type-specific effect of myostatin on myogenic regulatory factors (MRFs), we examined mRNA expression of MRFs in five skeletal muscles of normal (NM) and myostatin-deficient double-muscled (DM) adult Japanese Shorthorn cattle by quantitative reverse-transcribed PCR. Among the four MRFs, namely, Myf5, MyoD, myogenin, and MRF4, MyoD expression was different among the muscles of the DM cattle (P < 0.01) but not of the NM cattle. Meanwhile, MyoD expression was significantly elevated only in masseter (MS) muscle in the DM cattle due to the myostatin deficiency (P < 0.05). Myf5 and MRF4 expression in semitendinosus (ST) was higher in the DM than in the NM cattle (P < 0.05). According to analysis of myosin heavy chain (MyHC) isoform expression, more MyHC-2x and -2a and less -slow isoforms were expressed in the longissimus and ST muscles compared to the MS muscle in both cattle (P < 0.05), but no significant difference in MyHC expression was observed between the NM and DM cattle. Taken together, myostatin has influences on Myf5 and MRF4 expression in faster-type muscles and on MyoD expression in slower-type muscles, suggesting a possible muscle type-specific effect of myostatin in skeletal muscle growth and maintenance. Animal science journal = Nihon chikusan Gakkaiho 80 6 678 85 20091200 10.1111/j.1740-0929.2009.00684.x 20163658 masatomiyake/published_papers/34661939 Yasuhiro Nagai Hideki Ogasawara Yoshikazu Taketa Hisashi Aso Takashi Kanaya Masato Miyake Kouichi Watanabe Shyuichi Ohwada Yoshihiro Muneta Takahiro Yamaguchi Expression of inflammatory-related factors in porcine anterior pituitary-derived cell line. Recent studies have shown that undifferentiated stem cells act as immunomodulators. To investigate the immunomodulatory function of the progenitor cells of the anterior pituitary gland, we attempted to establish a stem/progenitor cell line from the porcine anterior pituitary gland, and to detail its inflammatory cytokine expression. A cloned cell line from the porcine anterior pituitary gland was established and was designated as the porcine anterior pituitary-derived cell line (PAPC). PAPC expressed the mRNA of Nanog and Oct-4, and showed positive immunoreactivity for beta-catenin and Hes1 in its nucleus. PAPC grew stably by repeated passage and rapidly in the EGF and bFGF containing medium. RT-PCR showed that PAPC expressed mRNA of IL-1alpha, IL-6, IL-12, IL-15, IL-18 and TLR4. PAPC expressed S100alpha and IL-18 protein, which was localized in the marginal epithelial cells of Rathke's pouch. These results suggest that PAPC is a stem/progenitor cell and may regulate anterior pituitary cell function through an immuno-endocrine pathway. Veterinary immunology and immunopathology 124 3-4 201 8 20080815 10.1016/j.vetimm.2008.03.007 18440649 masatomiyake/published_papers/31975137 Shinichiro Hayashi Masato Miyake Kouichi Watanabe Hisashi Aso Seigo Hayashi Shyuichi Ohwada Takahiro Yamaguchi Myostatin preferentially down-regulates the expression of fast 2x myosin heavy chain in cattle. Myostatin is involved in an inhibitor of muscular growth and differentiation. Myoblasts derived from double-muscled Japanese shorthorn cattle (DM myoblasts) with absence of functional myostatin had higher abilities to proliferate and differentiate than myoblasts derived from normal-muscled cattle (NM myoblasts). In DM myoblasts, mRNA expressions of fetal myosin heavy chain (MyHC) in growth medium and of fast 2a and 2x MyHC in fusion medium were significantly greater than that in NM myoblasts. No significant difference existed in expressions of embryonic and slow MyHC mRNA between DM and NM myoblasts. The expression of MyoD mRNA was suppressed in myoblasts by administration of myostatin. Two cloned DM myoblast strains (DMc) were established. Addition of myostatin for DMc resulted in less myotube formation and suppression of mRNA expression of fast 2x MyHC. These findings suggest that the endogenous myostatin preferentially down-regulates the expression of the fast 2x MyHC and participates in differentiation of myofiber types during early bovine myogenesis. Proceedings of the Japan Academy. Series B, Physical and biological sciences 1349-2896 84 8 354 62 20080000 18941308 masatomiyake/published_papers/31975139 Masato Miyake Shinichiro Hayashi Tomomi Sato Yoshikazu Taketa Kouichi Watanabe Shinji Hayashi Sachi Tanaka Shyuichi Ohwada Hisashi Aso Takahiro Yamaguchi Myostatin and MyoD family expression in skeletal muscle of IGF-1 knockout mice. Insulin-like growth factor-1 (IGF-1) is a positive regulator in proliferation and differentiation of skeletal muscle cells, while myostatin (MSTN) is a member of transforming growth factor beta superfamily that acts as a negative regulator of skeletal muscle mass. The present study was performed to detail whether a correlation exists between MSTN and IGF-1 in skeletal muscle of IGF-1 knockout mice (IGF-1(-/-)) and their wild type (WT; i.e., IGF-1(+/+)) littermates. The body weight of IGF-1(-/-) animals was 32% that of WT littermates. The fiber cross-sectional areas (CSA) and number of fibers in M. rectus femoris of IGF-1(-/-) animals were 49 and 59% those of WT animals, respectively. Thus, muscle hypoplasia of IGF-1(-/-) undoubtedly was confirmed. Myostatin mRNA levels and protein levels were similar between M. gastrocnemius of IGF-1(-/-) and WT animals. Myostatin immunoreactivity was similarly localized in muscle fibers of both IGF-1(-/-) and WT M. rectus femoris. The mRNA levels of MyoD family (Myf5, MyoD, MRF4, myogenin) were differentially expressed in IGF-1(-/-)M. gastrocnemius, in which the mRNA expression of MRF4 and myogenin was significantly lower, whereas there were no changes in the mRNA expression of Myf5 and MyoD. These findings first describe that myostatin expression is not influenced by intrinsic failure of IGF-1, although MRF4 and myogenin are downregulated. Cell biology international 1065-6995 31 10 1274 9 20071000 17590360 masatomiyake/misc/40893432 Sachi Tanaka Yasuhiro Nagai Yoko Noguchi Masato Miyake Kouichi Watanabe Shyuichi Ohwada Hisashi Aso Takahiro Yamaguchi Differential cytokine expression in T cell subsets from bovine peripheral blood ANIMAL SCIENCE JOURNAL 1344-3941 79 5 597 604 20081000 10.1111/j.1740-0929.2008.00569.x masatomiyake/misc/38525107 TAKETA Yoshikazu NAGAI Yasuhiro OGASAWARA Hideki HAYASHI Shinichiro MIYAKE Masato TANAKA Sachi WATANABE Kouichi OHWADA Shyuichi ASO Hisashi YAMAGUCHI Takahiro Differential expression of myostatin and its receptor in the porcine anterior pituitary gland Animal science journal 1344-3941 79 3 382 390 20080601 masatomiyake/presentations/48309350 脂肪細胞におけるストレス応答シグナルとGDF15を介した食欲制御 第45回日本肥満学会 20241019 masatomiyake/presentations/48491875 三宅雅人 膵β細胞株への野生型およびAkita変異インスリン発現の影響と 小胞体ストレス応答の役割 第67回日本糖尿病学会年次学術集会 20240519 masatomiyake/presentations/48309335 脂肪細胞のストレス応答シグナルから発する食欲制御 第58回糖尿病学の進歩 20240217 masatomiyake/presentations/48492176 小胞体タンパク質恒常性を改善して インスリン合成を向上させる 新規低分子化合物の同定 第34回分子糖尿病学シンポジウム 20231202 masatomiyake/presentations/48309340 2型糖尿病へと至る膵β細胞の小胞体プロテオスタシス変容と創薬 第17回日本臨床ストレス応答学会大会 20231118 日本糖尿病学会 若手研究奨励賞 20180500 日本臨床ストレス応答学会 若手研究奨励賞 20151000 分子糖尿病学研究会 若手研究奨励賞 20121200 東北大学 研究科長賞 20100300 日本畜産学会 優秀発表賞 20070300