研究等業績 - 原著論文 - 脇　裕典

Immune checkpoint inhibitor restores daily function in patient with microsatellite instability (MSI)-high advanced endometrial cancer and poor performance status

Ayaka Matsui, Taichi Yoshida, Yuya Takahashi, Koji Fukuda, Kazuhiro Shimazu, Daiki Taguchi, Hanae Shinozaki, Naoaki Kodama, Shunsuke Kato, Hironori Waki, Hiroshi Nanjo, Hiroyuki Shibata

International Cancer Conference Journal ( Springer Science and Business Media LLC )    2025年02月  [査読有り]

研究論文（学術雑誌）  

Abstract

The immune checkpoint system suppresses T-cell activity. Unlike cytotoxic anticancer drugs that directly kill cells, immune checkpoint inhibitors (ICIs) are generally safer by stimulating tumor immunity. However, most clinical trials require patients to have a better performance status (PS), leaving limited evidence for those with poorer PS. In practice, patients may be classified with poor PS due to tumor-induced pain and motor dysfunction, even if major organs remain functional. Real-world data on non-small cell lung cancer has shown no safety difference between patients with PS 3/4 and those with lower PS. Approximately 20–30% of endometrial cancer cases show microsatellite instability-high (MSI-high), the highest among common malignancies. A 46-year-old patient with advanced, recurrent endometrial cancer resistant to standard chemotherapy, and PS of 4 from severe pelvic pain, was diagnosed with MSI-high. Pembrolizumab was initiated and continued for 19 courses, after which lesions had disappeared or calcified, leading to drug discontinuation. Now, 4 and a half years post-treatment, she has regained independent mobility and returned to work, and her PS has improved to approximately 1. Side effects included Grade 2 or lower thyroiditis, hypothyroidism, and hypoadrenalism, manageable with hormone replacement therapy and temporary pembrolizumab suspension. This case underscores the need to test for MSI-high/mismatch repair deficiency in endometrial cancer and to consider ICI therapy in patients with poor PS but no major organ dysfunction. In such cases, ICI can rapidly improve overall condition, a phenomenon known as a Lazarus-type response, as seen in other cancers such as non-small cell lung cancer.

DOI

GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.

Kana Sasaki, Hiroki Fujita, Takehiro Sato, Shunske Kato, Yuya Takahashi, Yukio Takeshita, Takashi Kanda, Takashi Saito, Takamori C Saido, Satoko Hattori, Yasukazu Hozumi, Yuichiro Yamada, Hironori Waki

Biochemical and biophysical research communications   741   151016 - 151016   2024年11月

研究論文（学術雑誌）  

The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, AppNL-G-F/NL-G-F mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of AppNL-G-F/NL-G-F mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.

DOI PubMed

Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.

Sanil Patel, Khatanzul Ganbold, Chung Hwan Cho, Juwairriyyah Siddiqui, Ramazan Yildiz, Njeri Sparman, Shani Sadeh, Christy M Nguyen, Jiexin Wang, Julian P Whitelegge, Susan K Fried, Hironori Waki, Claudio J Villanueva, Marcus M Seldin, Shinya Sakaguchi, Wilfried Ellmeier, Peter Tontonoz, Prashant Rajbhandari

Nature communications   15 ( 1 ) 8533 - 8533   2024年10月  [査読有り]

研究論文（学術雑誌）  

White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.

DOI PubMed

糖尿病の診療や生活の体験に関するアンケート調査

井花 庸子, 木村 晶子, 杉山 雄大, 今井 健二郎, 細野 知子, 堀田 裕子, 山本 行子, 相原 允一, 青山 倫久, 笹子 敬洋, 脇 裕典, 大杉 満, 植木 浩二郎, 山内 敏正

糖尿病 ( (一社)日本糖尿病学会 )  67 ( 11 ) 476 - 488   2024年09月  [査読有り]

研究論文（学術雑誌）  

Recurrent nocturnal hypoglycemic hemiplegia: a case report and review of the literature.

Hanako Toyama, Kazuyuki Takahashi, Tatsunori Shimizu, Izumi Otaka, Sakiko Abe, Shunsuke Kato, Sayaka Ando, Takehiro Sato, Tsukasa Morii, Hiroki Fujita, Hironori Waki

Endocrine journal ( Japan Endocrine Society )  71 ( 4 ) 409 - 416   2024年02月  [査読有り]

研究論文（学術雑誌）  

A 67-year-old man with type 1 diabetes, Cronkhite-Canada syndrome, and membranous nephropathy who received insulin therapy was admitted to our hospital with right hemiplegia and dysarthria. Brain magnetic resonance imaging revealed a lesion with a high diffusion-weighted imaging signal and low apparent diffusion coefficient signal in the posterior limb of the left internal capsule. He was hypoglycemic with a blood glucose level of 56 mg/dL (3.1 mmol/L). Following glucose administration, the patient's symptoms resolved within several hours. The patient experienced similar transient hypoglycemic hemiplegia at midnight, three times within 10 days. In a literature review of 170 cases of hypoglycemic hemiplegia, 26 cases of recurrent hemiplegia were investigated. Recurrent hypoglycemic hemiplegia occurs more frequently on the right side than on the left side, and most recurrences occur within approximately a week, almost exclusively at midnight and in the early morning. We speculate that hypoglycemia-associated autonomic failure may be involved in the nocturnal recurrence of episodes. In our patient, depleted endogenous insulin secretion and lipodystrophy at the injection site, may have acted as additional factors, leading to severe hypoglycemia despite the absence of apparent autonomic neuropathy. Clinically, it is important to recognize hypoglycemia as a cause of hemiplegia to avoid unnecessary intervention and to maintain an appropriate blood glucose level at midnight and early in the morning to prevent recurrent hypoglycemic hemiplegia.

DOI PubMed

Efficacy of StepAdd, a Personalized mHealth Intervention Based on Social Cognitive Theory to Increase Physical Activity Among Patients With Type 2 Diabetes Mellitus: Protocol for a Randomized Controlled Trial.

Kayo Waki, Yuya Tsurutani, Hironori Waki, Syunpei Enomoto, Kosuke Kashiwabara, Akira Fujiwara, Kazuki Orime, Sho Kinguchi, Toshimasa Yamauchi, Nobuhito Hirawa, Kouichi Tamura, Yasuo Terauchi, Masaomi Nangaku, Kazuhiko Ohe

JMIR research protocols   13   e53514   2024年02月

研究論文（学術雑誌）  

BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

DOI PubMed

Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia.

Yuya Takahashi, Hiroki Fujita, Yusuke Seino, Satoko Hattori, Shihomi Hidaka, Tsuyoshi Miyakawa, Atsushi Suzuki, Hironori Waki, Daisuke Yabe, Yutaka Seino, Yuichiro Yamada

Journal of cachexia, sarcopenia and muscle ( Wiley )  14 ( 6 ) 2703 - 2718   2023年10月

研究論文（学術雑誌）  

BACKGROUND: Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. METHODS: Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr-/- ) and wild-type (Gipr+/+ ) mice. FAPs isolated from lower limb muscles of 12-week-old Gipr+/+ mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice after glycerol injection into the TA muscles. RESULTS: Body composition analysis revealed that 104-week-old Gipr-/- mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P < 0.05 vs. 104-week-old Gipr+/+ mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P < 0.05 vs. 104-week-old Gipr+/+ mice). Eighty-four-week-old Gipr-/- mice exhibited increases in grip strength (P < 0.05), weights of TA (P < 0.05), soleus (P < 0.01), gastrocnemius (P < 0.05) and quadriceps femoris (P < 0.01) muscles, and average TA muscle fibre CSA (P < 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin-positive cells (P < 0.0001) compared with 84-week-old Gipr+/+ mice. Oil Red O staining analysis revealed 1.6- and 1.7-fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P < 0.01 and P < 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr-/- mice and GIP receptor antagonist-treated Gipr+/+ mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P < 0.001 and P < 0.01 vs. untreated Gipr+/+ mice, respectively) and increased average TA muscle fibre CSA (P < 0.01 and P < 0.05 vs. untreated Gipr+/+ mice, respectively). CONCLUSIONS: GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

DOI PubMed

NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis.

Yuta Hiraike, Kaede Saito, Misato Oguchi, Takahito Wada, Gotaro Toda, Shuichi Tsutsumi, Kana Bando, Junji Sagawa, Gaku Nagano, Haruya Ohno, Naoto Kubota, Tetsuya Kubota, Hiroyuki Aburatani, Takashi Kadowaki, Hironori Waki, Shintaro Yanagimoto, Toshimasa Yamauchi

Proceedings of the National Academy of Sciences of the United States of America   120 ( 31 ) e2308750120   2023年08月

研究論文（学術雑誌）  

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.

DOI PubMed

Relationships among Postprandial Plasma Active GLP-1 and GIP Excursions, Skeletal Muscle Mass, and Body Fat Mass in Patients with Type 2 Diabetes Treated with Either Miglitol, Sitagliptin, or Their Combination: A Secondary Analysis of the MASTER Study.

Masahiro Sato, Hiroki Fujita, Hiroki Yokoyama, Atsushi Mikada, Yohei Horikawa, Yuya Takahashi, Yuichiro Yamada, Hironori Waki, Takuma Narita

Journal of clinical medicine ( MDPI AG )  12 ( 9 ) 3104 - 3104   2023年04月

研究論文（学術雑誌）  

BACKGROUND: We previously conducted a pilot randomized controlled trial "the MASTER study" and demonstrated that alpha-glucosidase inhibitor miglitol and a dipeptidyl peptidase-4 inhibitor sitagliptin modified postprandial plasma excursions of active glucagon-like peptide-1 (aGLP-1) and active gastric inhibitory polypeptide (aGIP), and miglitol treatment decreased body fat mass in patients with type 2 diabetes (T2D). However, the details regarding the relationships among postprandial plasma aGLP-1 and aGIP excursions, skeletal muscle mass, and body fat mass are unclear. METHODS: We conducted a secondary analysis of the relationships among skeletal muscle mass index (SMI), total body fat mass index (TBFMI), and the incremental area under the curves (iAUC) of plasma aGLP-1 and aGIP excursions following mixed meal ingestion at baseline and after 24-week add-on treatment with either miglitol alone, sitagliptin alone, or their combination in T2D patients. RESULTS: SMI was not changed after the 24-week treatment with miglitol and/or sitagliptin. TBFMI was reduced and the rates of aGIP-iAUC change were lowered in the two groups treated with miglitol, although their correlations did not reach statistical significance. We observed a positive correlation between the rates of aGIP-iAUC and TBFMI changes and a negative correlation between the rates of TBFMI and SMI changes in T2D patients treated with sitagliptin alone whose rates of aGIP-iAUC change were elevated. CONCLUSIONS: Collectively, although T2D patients treated with miglitol and/or sitagliptin did not show altered SMI after 24-week treatment, the current study suggests that there are possible interrelationships among postprandial plasma aGIP excursion modified by sitagliptin, skeletal muscle mass, and body fat mass.

DOI PubMed

Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling.

Yusuke Adachi, Kazutaka Ueda, Seitaro Nomura, Kaoru Ito, Manami Katoh, Mikako Katagiri, Shintaro Yamada, Masaki Hashimoto, Bowen Zhai, Genri Numata, Akira Otani, Munetoshi Hinata, Yuta Hiraike, Hironori Waki, Norifumi Takeda, Hiroyuki Morita, Tetsuo Ushiku, Toshimasa Yamauchi, Eiki Takimoto, Issei Komuro

Nature communications   13 ( 1 ) 5117 - 5117   2022年09月  [査読有り]

研究論文（学術雑誌）  

Although inflammation plays critical roles in the development of atherosclerosis, its regulatory mechanisms remain incompletely understood. Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, we show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response and thus vascular remodeling as a protective mechanism. In a mouse model of endovascular injury, macrophages accumulate in PVAT, causing beiging phenotype change. Inhibition of PVAT beiging by genetically silencing PRDM16, a key regulator to beiging, exacerbates inflammation and vascular remodeling following injury. Conversely, activation of PVAT beiging attenuates inflammation and pathological vascular remodeling. Single-cell RNA sequencing reveals that beige adipocytes abundantly express neuregulin 4 (Nrg4) which critically regulate alternative macrophage activation. Importantly, significant beiging is observed in the diseased aortic PVAT in patients with acute aortic dissection. Taken together, vascular injury induces the beiging of adjacent PVAT with macrophage accumulation, where NRG4 secreted from the beige PVAT facilitates alternative activation of macrophages, leading to the resolution of vascular inflammation. Our study demonstrates the pivotal roles of PVAT in vascular inflammation and remodeling and will open a new avenue for treating atherosclerosis.

DOI PubMed

NFIA determines the cis-effect of genetic variation on Ucp1 expression in murinethermogenic adipocytes

Yuta Hiraike, Shuichi Tsutsumi, Takahito Wada, Misato Oguchi, Kaede Saito, Masahiro Nakamura, Satoshi Ota, Michinori Koebis, Harumi Nakao, Atsu Aiba, Gaku Nagano, Haruya Ohno, Kenji Oki, Masayasu Yoneda, Takashi Kadowaki, Hiroyuki Aburatani, Hironori Waki, Toshimasa Yamauchi

iScience ( Elsevier BV )  25 ( 8 ) 104729 - 104729   2022年08月  [査読有り]

研究論文（学術雑誌）  

Thermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via uncoupling protein-1 (Ucp1). However, the effect of genetic variation on these cells, a major source of disease susceptibility, has been less well studied. Here we examined beige adipocytes from obesity-prone C57BL/6J (B6) and obesity-resistant 129X1/SvJ (129) mouse strains and identified a cis-regulatory variant rs47238345 that is responsible for differential Ucp1 expression. The alternative T allele of rs47238345 at the Ucp1 -12kb enhancer in 129 facilitates the allele-specific binding of nuclear factor I-A (NFIA) to mediate allele-specific enhancer-promoter interaction and Ucp1 transcription. Furthermore, CRISPR-Cas9/Cpf1-mediated single nucleotide polymorphism (SNP) editing of rs47238345 resulted in increased Ucp1 expression. We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as a trans-acting regulator of Ucp1 in mice and humans. These results demonstrate the cis- and trans-acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.

DOI PubMed

A Pilot Study to Assess Glucose, Insulin, and Incretin Responses Following Novel High Resistant Starch Rice Ingestion in Healthy Men.

Kazuyuki Takahashi, Hiroki Fujita, Naoko Fujita, Yuya Takahashi, Shunsuke Kato, Tatsunori Shimizu, Yumi Suganuma, Takehiro Sato, Hironori Waki, Yuichiro Yamada

Diabetes therapy : research, treatment and education of diabetes and related disorders   13 ( 7 ) 1383 - 1393   2022年07月  [査読有り]

研究論文（学術雑誌）  

INTRODUCTION: A newly developed resistant starch (RS) rice line with double mutation of starch synthase IIIa and branching enzyme IIb (ss3a/be2b) exhibits a tenfold greater percentage RS value than the wild-type rice line. Currently, the effects of cooked rice with such high RS content on secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are unclear. Therefore, we conducted a pilot study to assess postprandial responses of GLP-1 and GIP along with glucose and insulin and also gastric emptying after ingestion of the high-RS cooked rice with ss3a/be2b in healthy subjects. METHODS: In a non-randomized crossover design, five healthy men ingested two test foods, control (low-RS) and high-RS cooked rice, with at least 1-week washout period between testing days. Plasma glucose, serum insulin, plasma total GLP-1, plasma total GIP, and also gastric emptying rate were measured after ingestion of each test food, and the incremental area under the curves (iAUC) was calculated for each biochemical parameter using the values from 0 to 180 min after ingestion. RESULTS: The high-RS cooked rice ingestion tended to reduce iAUC-glucose (p = 0.06) and significantly reduced iAUC-insulin (p < 0.01) and iAUC-GLP-1 (p < 0.05) but not iAUC-GIP (p = 0.21) relative to control cooked rice ingestion. In addition, the high-RS cooked rice ingestion did not affect gastric emptying. CONCLUSIONS: The present results indicate that the suppressive effects of the high-RS cooked rice ingestion on postprandial responses of glucose and insulin may be provided through attenuation in GLP-1 secretion along with its low digestibility into glucose. We suggest that the high-RS rice with ss3a/be2b may serve as a better carbohydrate source and also as a novel functional food for dietary interventions to improve postprandial hyperglycemia and hyperinsulinemia without both enhancing GLP-1 secretion and affecting gastric emptying in patients with diabetes.

DOI PubMed

Cases of fulminant type 1 and type 2 diabetes mellitus whose HbA1c levels were unmeasurable due to increased labile HbA1c

Shunsuke Kato, Izumi Otaka, Hanako Toyama, Ryota Kusumi, Kazuyuki Takahashi, Mitsuhiko Nara, Yumi Suganuma, Takehiro Sato, Tsukasa Morii, Hiroki Fujita, Hironori Waki

Diabetology International ( Springer Science and Business Media LLC )  13 ( 4 ) 698 - 703   2022年07月  [査読有り]

研究論文（学術雑誌）  

DOI

Pick the best of both glucose and lipid metabolism.

Tatsunori Shimizu, Yuya Takahashi, Hiroki Fujita, Hironori Waki

Journal of diabetes investigation     2022年02月

研究論文（学術雑誌）  

DOI PubMed

A Case of Chronic Intestinal Pseudo-obstruction with Mitochondrial Diseases.

Takanobu Jinnouchi, Yoshitaka Sakurai, Kengo Miyoshi, Chie Koizumi, Hironori Waki, Naoto Kubota, Toshimasa Yamauchi

Internal medicine (Tokyo, Japan)   61 ( 4 ) 469 - 474   2021年08月  [査読有り]

研究論文（学術雑誌）  

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of intestinal dysmotility characterized by chronic symptoms, including vomiting and abdominal pain, associated with bowel obstruction without any mechanical obstructive causes. We herein report a case of mitochondrial diseases with recurrent duodenal obstruction that was initially diagnosed as superior mesenteric artery syndrome (SMAS) for a few years but was later diagnosed as CIPO. Since CIPO is known to be associated with mitochondrial diseases, it should be considered in the differential diagnosis of patients with mitochondrial diseases presenting with recurrent intestinal obstruction.

DOI PubMed

Pseudo-hyperglucagonemia was observed in pancreatectomized patients when measured by glucagon sandwich enzyme-linked immunosorbent assay.

Masaki Kobayashi, Hironori Waki, Hitomi Nakayama, Atsushi Miyachi, Eri Mieno, Hitoshi Hamajima, Moritaka Goto, Kentaro Yamada, Toshimasa Yamauchi, Takashi Kadowaki, Tadahiro Kitamura

Journal of diabetes investigation   12 ( 2 ) 286 - 289   2021年02月  [査読有り]

研究論文（学術雑誌）  

Glucagon is detected in plasma even after total pancreatectomy, and it is debated whether this glucagon is derived from the gastrointestinal tract. Here, we applied sandwich enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-high-resolution mass spectrometry to measure plasma glucagon levels in one patient after partial pancreatectomy (one-seventh of the pancreas remaining) and three patients after total pancreatectomy. Sandwich ELISA detected higher glucagon levels in pancreatectomy patients than in healthy individuals. In contrast, liquid chromatography-high-resolution mass spectrometry showed that plasma glucagon levels in pancreatectomy patients were below the lower limit of quantification. Plasma glucagon measured by sandwich ELISA showed a striking correlation with plasma glicentin, suggesting cross-reaction with this gastrointestinal glucagon-related peptide. These results indicated that pancreatectomized patients falsely showed pseudo-hyperglucagonemia when measured by glucagon sandwich ELISA.

DOI PubMed

Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance.

Jun Hosoe, Fuyuki Miya, Hiroko Kadowaki, Toyofumi Fujiwara, Ken Suzuki, Takashi Kato, Hironori Waki, Takayoshi Sasako, Katsuya Aizu, Natsumi Yamamura, Fusako Sasaki, Makoto Kurano, Kazuo Hara, Masaki Tanaka, Hiroyuki Ishiura, Shoji Tsuji, Kenjiro Honda, Jun Yoshimura, Shinichi Morishita, Fumiko Matsuzawa, Sei-Ichi Aikawa, Keith A Boroevich, Masaomi Nangaku, Yukinori Okada, Tatsuhiko Tsunoda, Nobuhiro Shojima, Toshimasa Yamauchi, Takashi Kadowaki

Diabetes research and clinical practice   169   108461 - 108461   2020年09月  [査読有り]

研究論文（学術雑誌）  

AIMS: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants. METHODS: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data. RESULTS: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance. CONCLUSIONS: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

DOI PubMed

NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation.

Yuta Hiraike, Hironori Waki, Kana Miyake, Takahito Wada, Misato Oguchi, Kaede Saito, Shuichi Tsutsumi, Hiroyuki Aburatani, Toshimasa Yamauchi, Takashi Kadowaki

PLoS genetics   16 ( 9 ) e1009044   2020年09月  [査読有り]

研究論文（学術雑誌）  

The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA-but not deletion mutant lacking pro#3 domain-rescued impaired expression of PPARγ, the master transcriptional regulator of adipogenesis and impaired adipocyte differentiation in NFIA-knockout cells. Mechanistically, the ability of NFIA to penetrate chromatin and bind to the crucial Pparg enhancer is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to repress expression of MyoD, the master transcriptional regulator of myogenesis as well as proximally transcribed non-coding RNA called DRReRNA, via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on PPARγ expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown and beige adipocyte differentiation.

DOI PubMed

Diabetes care providers' manual for disaster diabetes care.

Jo Satoh, Koichi Yokono, Rie Ando, Toshinari Asakura, Kazuhiko Hanzawa, Yasushi Ishigaki, Takashi Kadowaki, Masato Kasuga, Hideki Katagiri, Yasuhisa Kato, Koreyuki Kurosawa, Masanobu Miura, Jiro Nakamura, Koichi Nishitsuka, Susumu Ogawa, Tomoko Okamoto, Sadanori Sakuma, Shigeru Sakurai, Hiroaki Satoh, Hidetoshi Shimauchi, Hiroaki Shimokawa, Wataru Shoji, Takashi Sugiyama, Akira Suwabe, Masahiro Tachi, Kazuma Takahashi, Susumu Takahashi, Yasuo Terayama, Hiroaki Tomita, Yoko Tsuchiya, Hironori Waki, Tsuyoshi Watanabe, Kazuaki Yahata, Hidetoshi Yamashita

Diabetology international   10 ( 3 ) 153 - 179   2019年07月  [査読有り]

研究論文（学術雑誌）  

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

DOI PubMed

Diabetes Care Providers' Manual for Disaster Diabetes Care.

Jo Satoh, Koichi Yokono, Rie Ando, Toshinari Asakura, Kazuhiko Hanzawa, Yasushi Ishigaki, Takashi Kadowaki, Masato Kasuga, Hideki Katagiri, Yasuhisa Kato, Koreyuki Kurosawa, Masanobu Miura, Jiro Nakamura, Koichi Nishitsuka, Susumu Ogawa, Tomoko Okamoto, Sadanori Sakuma, Shigeru Sakurai, Hiroaki Satoh, Hidetoshi Shimauchi, Hiroaki Shimokawa, Wataru Shoji, Takashi Sugiyama, Akira Suwabe, Masahiro Tachi, Kazuma Takahashi, Susumu Takahashi, Yasuo Terayama, Hiroaki Tomita, Yoko Tsuchiya, Hironori Waki, Tsuyoshi Watanabe, Kazuaki Yahata, Hidetoshi Yamashita

Journal of diabetes investigation   10 ( 4 ) 1118 - 1142   2019年07月  [査読有り]

研究論文（学術雑誌）  

To ensure that experiences and lessons learned from the unprecedented 2011 Great East Japan Earthquake are used to improve future disaster planning, the Japan Diabetes Society (JDS) launched the "Research and Survey Committee for Establishing Disaster Diabetes Care Systems Based on Relevant Findings from the Great East Japan Earthquake" under the supervision of the Chairman of the JDS. The Committee conducted a questionnaire survey among patients with diabetes, physicians, disaster medical assistance teams (DMATs), nurses, pharmacists, and nutritionists in disaster areas about the events they saw happening, the situations they found difficult to handle, and the needs that they felt required to be met during the 2011 Great East Japan Earthquake. A total of 3,481 completed questionnaires were received. Based on these and other experiences and lessons reported following the 2011 Great East Japan Earthquake and the 2004 Niigata-Chuetsu Earthquakes, the current "Manual for Disaster Diabetes Care" has been developed by the members of the Committee and other invited authors from relevant specialties. To our knowledge, the current Manual is the world's first to focus on emergency diabetes care, with this digest English version translated from the Japanese original. It is sincerely hoped that patients with diabetes and healthcare providers around the world will find this manual helpful in promoting disaster preparedness and implementing disaster relief.

DOI PubMed

Robust and highly efficient hiPSC generation from patient non-mobilized peripheral blood-derived CD34+ cells using the auto-erasable Sendai virus vector.

Takashi Okumura, Yumi Horie, Chen-Yi Lai, Huan-Ting Lin, Hirofumi Shoda, Bunki Natsumoto, Keishi Fujio, Eri Kumaki, Tsubasa Okano, Shintaro Ono, Kay Tanita, Tomohiro Morio, Hirokazu Kanegane, Hisanori Hasegawa, Fumitaka Mizoguchi, Kimito Kawahata, Hitoshi Kohsaka, Hiroshi Moritake, Hiroyuki Nunoi, Hironori Waki, Shin-Ichi Tamaru, Takayoshi Sasako, Toshimasa Yamauchi, Takashi Kadowaki, Hiroyuki Tanaka, Sachiko Kitanaka, Ken Nishimura, Manami Ohtaka, Mahito Nakanishi, Makoto Otsu

Stem cell research & therapy   10 ( 1 ) 185 - 185   2019年06月  [査読有り]

研究論文（学術雑誌）  

BACKGROUND: Disease modeling with patient-derived induced pluripotent stem cells (iPSCs) is a powerful tool for elucidating the mechanisms underlying disease pathogenesis and developing safe and effective treatments. Patient peripheral blood (PB) cells are used for iPSC generation in many cases since they can be collected with minimum invasiveness. To derive iPSCs that lack immunoreceptor gene rearrangements, hematopoietic stem and progenitor cells (HSPCs) are often targeted as the reprogramming source. However, the current protocols generally require HSPC mobilization and/or ex vivo expansion owing to their sparsity at the steady state and low reprogramming efficiencies, making the overall procedure costly, laborious, and time-consuming. METHODS: We have established a highly efficient method for generating iPSCs from non-mobilized PB-derived CD34+ HSPCs. The source PB mononuclear cells were obtained from 1 healthy donor and 15 patients and were kept frozen until the scheduled iPSC generation. CD34+ HSPC enrichment was done using immunomagnetic beads, with no ex vivo expansion culture. To reprogram the CD34+-rich cells to pluripotency, the Sendai virus vector SeVdp-302L was used to transfer four transcription factors: KLF4, OCT4, SOX2, and c-MYC. In this iPSC generation series, the reprogramming efficiencies, success rates of iPSC line establishment, and progression time were recorded. After generating the iPSC frozen stocks, the cell recovery and their residual transgenes, karyotypes, T cell receptor gene rearrangement, pluripotency markers, and differentiation capability were examined. RESULTS: We succeeded in establishing 223 iPSC lines with high reprogramming efficiencies from 15 patients with 8 different disease types. Our method allowed the rapid appearance of primary colonies (~ 8 days), all of which were expandable under feeder-free conditions, enabling robust establishment steps with less workload. After thawing, the established iPSC lines were verified to be pluripotency marker-positive and of non-T cell origin. A majority of the iPSC lines were confirmed to be transgene-free, with normal karyotypes. Their trilineage differentiation capability was also verified in a defined in vitro assay. CONCLUSION: This robust and highly efficient method enables the rapid and cost-effective establishment of transgene-free iPSC lines from a small volume of PB, thus facilitating the biobanking of patient-derived iPSCs and their use for the modeling of various diseases.

DOI PubMed

The RNA Methyltransferase Complex of WTAP, METTL3, and METTL14 Regulates Mitotic Clonal Expansion in Adipogenesis

Masatoshi Kobayashi, Mitsuru Ohsugi, Takayoshi Sasako, Motoharu Awazawa, Toshihiro Umehara, Aya Iwane, Naoki Kobayashi, Yukiko Okazaki, Naoto Kubota, Ryo Suzuki, Hironori Waki, Keiko Horiuchi, Takao Hamakubo, Tatsuhiko Kodama, Seiichiro Aoe, Kazuyuki Tobe, Takashi Kadowaki, Kohjiro Ueki

Molecular and Cellular Biology ( American Society for Microbiology )  38 ( 16 ) e00116 - 18   2018年06月  [査読有り]

研究論文（学術雑誌）  

<title>ABSTRACT</title>
Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the precise mechanism remains unclear. <italic>N</italic>⁶-Methyladenosine (m⁶A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA <italic>N</italic>⁶-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA <italic>in vitro</italic>. Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, <italic>Wtap</italic> heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.

DOI PubMed

NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program.

Yuta Hiraike, Hironori Waki, Jing Yu, Masahiro Nakamura, Kana Miyake, Gaku Nagano, Ryo Nakaki, Ken Suzuki, Hirofumi Kobayashi, Shogo Yamamoto, Wei Sun, Tomohisa Aoyama, Yusuke Hirota, Haruya Ohno, Kenji Oki, Masayasu Yoneda, Andrew P White, Yu-Hua Tseng, Aaron M Cypess, Therese J Larsen, Naja Z Jespersen, Camilla Scheele, Shuichi Tsutsumi, Hiroyuki Aburatani, Toshimasa Yamauchi, Takashi Kadowaki

Nature cell biology   19 ( 9 ) 1081 - 1092   2017年09月  [査読有り]

研究論文（学術雑誌）  

Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.

DOI PubMed

CDK5 Regulatory Subunit-Associated Protein 1-like 1 Negatively Regulates Adipocyte Differentiation through Activation of Wnt Signaling Pathway.

Kazumi Take, Hironori Waki, Wei Sun, Takahito Wada, Jing Yu, Masahiro Nakamura, Tomohisa Aoyama, Toshimasa Yamauchi, Takashi Kadowaki

Scientific reports   7 ( 1 ) 7326 - 7326   2017年08月  [査読有り]

研究論文（学術雑誌）  

CDK5 Regulatory Subunit-Associated Protein 1-like 1 (CDKAL1) was identified as a susceptibility gene for type 2 diabetes and body mass index in genome-wide association studies. Although it was reported that CDKAL1 is a methylthiotransferase essential for tRNALys(UUU) and faithful translation of proinsulin generated in pancreatic β cells, the role of CDKAL1 in adipocytes has not been understood well. In this study, we found that CDKAL1 is expressed in adipose tissue and its expression is increased during differentiation. Stable overexpression of CDKAL1, however, inhibited adipocyte differentiation of 3T3-L1 cells, whereas knockdown of CDKAL1 promoted differentiation. CDKAL1 increased protein levels of β-catenin and its active unphosphorylated form in the nucleus, thereby promoting Wnt target gene expression, suggesting that CDKAL1 activated the Wnt/β-catenin pathway-a well-characterized inhibitory regulator of adipocyte differentiation. Mutant experiments show that conserved cysteine residues of Fe-S clusters of CDKAL1 are essential for its anti-adipogenic action. Our results identify CDKAL1 as novel negative regulator of adipocyte differentiation and provide insights into the link between CDKAL1 and metabolic diseases such as type 2 diabetes and obesity.

DOI PubMed

Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner.

Junna Yamaguchi, Tetsuhiro Tanaka, Hisako Saito, Seitaro Nomura, Hiroyuki Aburatani, Hironori Waki, Takashi Kadowaki, Masaomi Nangaku

Scientific reports   7 ( 1 ) 6516 - 6516   2017年07月  [査読有り]

研究論文（学術雑誌）  

Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein β, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.

DOI PubMed

Previous dropout from diabetic care as a predictor of patients' willingness to use mobile applications for self-management: A cross-sectional study.

Satoko Yamaguchi, Kayo Waki, Nobuko Tomizawa, Hironori Waki, Yasuhito Nannya, Masaomi Nangaku, Takashi Kadowaki, Kazuhiko Ohe

Journal of diabetes investigation   8 ( 4 ) 542 - 549   2017年07月  [査読有り]

研究論文（学術雑誌）  

AIMS/INTRODUCTION: Preventing dropout is crucial in managing diabetes. Accordingly, we investigated whether patients who had dropped out of diabetic care are suitable candidates for the use of mobile technologies - such as smartphone applications - to support self-management (mHealth), which might help prevent dropout. MATERIALS AND METHODS: We carried out a cross-sectional study in Tokyo, Japan. Patients aged 20 years or older who were clinically diagnosed as diabetic and who regularly visited the outpatient unit at the University of Tokyo Hospital were recruited between August 2014 and March 2015. Data were collected through face-to-face structured interviews, physical measurements and medical records. Participants were asked whether they were willing to use mHealth after being shown DialBetics - an mHealth application for diabetics - as an example, and about their history of dropout and previous mHealth experience. Data were analyzed by multivariate logistic regression models. RESULTS: Of 307 patients with type 1 and type 2 diabetes, 34 (11.1%) had previously dropped out from diabetic care. Multivariate analysis identified previous mHealth experience as a negative predictor of dropout (odds ratio 0.211, P = 0.023). Of those 34 patients, 27 (79.4%) expressed willingness to use mHealth, a significantly higher percentage than for those who had never dropped out (51.5%, P = 0.002). After adjusting for confounders, history of dropout remained a strong predictor of willingness (odds ratio 3.870, P = 0.004). CONCLUSIONS: Patients who previously dropped out of diabetic care are suitable candidates for mHealth. Future studies must evaluate whether mHealth is effective for preventing repeated dropout and improving glycemic control among this population.

DOI PubMed

RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs.

Jiexin Wang, Prashant Rajbhandari, Andrey Damianov, Areum Han, Tamer Sallam, Hironori Waki, Claudio J Villanueva, Stephen D Lee, Ronni Nielsen, Susanne Mandrup, Karen Reue, Stephen G Young, Julian Whitelegge, Enrique Saez, Douglas L Black, Peter Tontonoz

The Journal of clinical investigation   127 ( 3 ) 987 - 1004   2017年03月  [査読有り]

研究論文（学術雑誌）  

A highly orchestrated gene expression program establishes the properties that define mature adipocytes, but the contribution of posttranscriptional factors to the adipocyte phenotype is poorly understood. Here we have shown that the RNA-binding protein PSPC1, a component of the paraspeckle complex, promotes adipogenesis in vitro and is important for mature adipocyte function in vivo. Cross-linking and immunoprecipitation followed by RNA sequencing revealed that PSPC1 binds to intronic and 3'-untranslated regions of a number of adipocyte RNAs, including the RNA encoding the transcriptional regulator EBF1. Purification of the paraspeckle complex from adipocytes further showed that PSPC1 associates with the RNA export factor DDX3X in a differentiation-dependent manner. Remarkably, PSPC1 relocates from the nucleus to the cytoplasm during differentiation, coinciding with enhanced export of adipogenic RNAs. Mice lacking PSPC1 in fat displayed reduced lipid storage and adipose tissue mass and were resistant to diet-induced obesity and insulin resistance due to a compensatory increase in energy expenditure. These findings highlight a role for PSPC1-dependent RNA maturation in the posttranscriptional control of adipose development and function.

DOI PubMed

Willingness of patients with diabetes to use an ICT-based self-management tool: a cross-sectional study.

Tomomi Shibuta, Kayo Waki, Nobuko Tomizawa, Ayumi Igarashi, Noriko Yamamoto-Mitani, Satoko Yamaguchi, Hideo Fujita, Shigeko Kimura, Katsuhito Fujiu, Hironori Waki, Yoshihiko Izumida, Takayoshi Sasako, Masatoshi Kobayashi, Ryo Suzuki, Toshimasa Yamauchi, Takashi Kadowaki, Kazuhiko Ohe

BMJ open diabetes research & care   5 ( 1 ) e000322   2017年  [査読有り]

研究論文（学術雑誌）  

OBJECTIVES: To examine the prevalence of the willingness of patients with diabetes to use a self-management tool based on information and communication technology (ICT) such as personal computers, smartphones, and mobile phones; and to examine the patient characteristics associated with that willingness. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional interview survey of 312 adults with diabetes at a university hospital in an urban area in Japan. Participants were classified into 2 groups: those who were willing to use an ICT-based self-management tool and those who were unwilling. Multiple logistic regression analysis was used to identify factors associated with the willingness, including clinical and social factors, current use of ICT, self-management practices, self-efficacy, and diabetes-related emotional distress. RESULTS: The mean age of the 312 participants was 66.3 years (SD=11.5) and 198 (63%) were male. Most of the participants (93%) had type 2 diabetes. Although only 51 (16%) currently used ICT-based self-management tools, a total of 157 (50%) expressed the willingness to use such a tool. Factors associated with the willingness included: not having nephropathy (OR=2.02, 95% CI 1.14 to 3.58); outpatient visits once a month or more (vs less than once a month, OR=2.13, 95% CI 1.13 to 3.99); current use of personal computers and/or smartphones (OR=4.91, 95% CI 2.69 to 8.98); and having greater diabetes-related emotional distress (OR=1.10, 95% CI 1.01 to 1.20). CONCLUSIONS: Approximately half of the patients showed interest in using an ICT-based self-management tool. Willing patients may expect ICT-based self-management tools to complement outpatient visits and to make self-management easier. Starting with patients who display the willingness factors might optimize programs based on such tools.

DOI PubMed

Small Molecule-Induced Complement Factor D (Adipsin) Promotes Lipid Accumulation and Adipocyte Differentiation.

No-Joon Song, Suji Kim, Byung-Hyun Jang, Seo-Hyuk Chang, Ui Jeong Yun, Ki-Moon Park, Hironori Waki, Dean Y Li, Peter Tontonoz, Kye Won Park

PloS one   11 ( 9 ) e0162228   2016年  [査読有り]

研究論文（学術雑誌）  

The epigenome and its role in diabetes.

Hironori Waki, Toshimasa Yamauchi, Takashi Kadowaki

Current diabetes reports   12 ( 6 ) 673 - 85   2012年12月  [査読有り]

研究論文（学術雑誌）  

Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation.

Hironori Waki, Masahiro Nakamura, Toshimasa Yamauchi, Ken-ichi Wakabayashi, Jing Yu, Lisa Hirose-Yotsuya, Kazumi Take, Wei Sun, Masato Iwabu, Miki Okada-Iwabu, Takanori Fujita, Tomohisa Aoyama, Shuichi Tsutsumi, Kohjiro Ueki, Tatsuhiko Kodama, Juro Sakai, Hiroyuki Aburatani, Takashi Kadowaki

PLoS genetics   7 ( 10 ) e1002311   2011年10月  [査読有り]

研究論文（学術雑誌）  

TLE3 is a dual-function transcriptional coregulator of adipogenesis.

Claudio J Villanueva, Hironori Waki, Cristina Godio, Ronni Nielsen, Wen-Ling Chou, Leo Vargas, Kevin Wroblewski, Christian Schmedt, Lily C Chao, Rima Boyadjian, Susanne Mandrup, Andrea Hevener, Enrique Saez, Peter Tontonoz

Cell metabolism   13 ( 4 ) 413 - 427   2011年04月  [査読有り]

研究論文（学術雑誌）  

Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis.

Takashi Kadowaki, Toshimasa Yamauchi, Hironori Waki, Masato Iwabu, Miki Okada-Iwabu, Masahiro Nakamura

Cold Spring Harbor symposia on quantitative biology   76   257 - 65   2011年  [査読有り]

研究論文（学術雑誌）  

The small molecule phenamil is a modulator of adipocyte differentiation and PPARgamma expression.

Kye Won Park, Hironori Waki, Sung-Pil Choi, Ki-Moon Park, Peter Tontonoz

Journal of lipid research   51 ( 9 ) 2775 - 84   2010年09月  [査読有り]

研究論文（学術雑誌）  

Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.

Masato Iwabu, Toshimasa Yamauchi, Miki Okada-Iwabu, Koji Sato, Tatsuro Nakagawa, Masaaki Funata, Mamiko Yamaguchi, Shigeyuki Namiki, Ryo Nakayama, Mitsuhisa Tabata, Hitomi Ogata, Naoto Kubota, Iseki Takamoto, Yukiko K Hayashi, Naoko Yamauchi, Hironori Waki, Masashi Fukayama, Ichizo Nishino, Kumpei Tokuyama, Kohjiro Ueki, Yuichi Oike, Satoshi Ishii, Kenzo Hirose, Takao Shimizu, Kazushige Touhara, Takashi Kadowaki

Nature   464 ( 7293 ) 1313 - 9   2010年04月  [査読有り]

研究論文（学術雑誌）  

The small molecule phenamil induces osteoblast differentiation and mineralization.

Kye Won Park, Hironori Waki, Woo-Kyun Kim, Brandon S J Davies, Stephen G Young, Farhad Parhami, Peter Tontonoz

Molecular and cellular biology   29 ( 14 ) 3905 - 14   2009年07月  [査読有り]

研究論文（学術雑誌）  

The expression of GPIHBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by peroxisome proliferator-activated receptor-gamma.

Brandon S J Davies, Hironori Waki, Anne P Beigneux, Emily Farber, Michael M Weinstein, Damien C Wilpitz, Li-Jung Tai, Ronald M Evans, Loren G Fong, Peter Tontonoz, Stephen G Young

Molecular endocrinology   22 ( 11 ) 2496 - 504   2008年11月  [査読有り]

研究論文（学術雑誌）  

Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation.

Kye Won Park, Hironori Waki, Claudio J Villanueva, Laurel A Monticelli, Cynthia Hong, Sona Kang, Ormond A MacDougald, Ananda W Goldrath, Peter Tontonoz

Molecular endocrinology   22 ( 9 ) 2038 - 48   2008年09月  [査読有り]

研究論文（学術雑誌）  

Selective purification and characterization of adiponectin multimer species from human plasma.

Yusuke Hada, Toshimasa Yamauchi, Hironori Waki, Atsushi Tsuchida, Kazuo Hara, Hirokazu Yago, Osamu Miyazaki, Hiroyuki Ebinuma, Takashi Kadowaki

Biochemical and biophysical research communications   356 ( 2 ) 487 - 93   2007年05月  [査読有り]

研究論文（学術雑誌）  

STAMPing out Inflammation.

Hironori Waki, Peter Tontonoz

Cell   129 ( 3 ) 451 - 2   2007年05月

研究論文（学術雑誌）  

The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression.

Hironori Waki, Kye Won Park, Nico Mitro, Liming Pei, Robert Damoiseaux, Damien C Wilpitz, Karen Reue, Enrique Saez, Peter Tontonoz

Cell metabolism   5 ( 5 ) 357 - 70   2007年05月  [査読有り]

研究論文（学術雑誌）  

Endocrine functions of adipose tissue.

Hironori Waki, Peter Tontonoz

Annual review of pathology   2   31 - 56   2007年

研究論文（学術雑誌）  

NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism.

Liming Pei, Hironori Waki, Bhavapriya Vaitheesvaran, Damien C Wilpitz, Irwin J Kurland, Peter Tontonoz

Nature medicine   12 ( 9 ) 1048 - 55   2006年09月  [査読有り]

研究論文（学術雑誌）  

Generation of globular fragment of adiponectin by leukocyte elastase secreted by monocytic cell line THP-1.

Hironori Waki, Toshimasa Yamauchi, Junji Kamon, Shunbun Kita, Yusuke Ito, Yusuke Hada, Shoko Uchida, Atsushi Tsuchida, Sato Takekawa, Takashi Kadowaki

Endocrinology   146 ( 2 ) 790 - 6   2005年02月  [査読有り]

研究論文（学術雑誌）  

Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.

Hironori Waki, Toshimasa Yamauchi, Junji Kamon, Yusuke Ito, Shoko Uchida, Shunbun Kita, Kazuo Hara, Yusuke Hada, Francis Vasseur, Philippe Froguel, Satoshi Kimura, Ryozo Nagai, Takashi Kadowaki

The Journal of biological chemistry   278 ( 41 ) 40352 - 63   2003年10月  [査読有り]

研究論文（学術雑誌）  

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.

Toshimasa Yamauchi, Junji Kamon, Yusuke Ito, Atsushi Tsuchida, Takehiko Yokomizo, Shunbun Kita, Takuya Sugiyama, Makoto Miyagishi, Kazuo Hara, Masaki Tsunoda, Koji Murakami, Toshiaki Ohteki, Shoko Uchida, Sato Takekawa, Hironori Waki, Nelson H Tsuno, Yoichi Shibata, Yasuo Terauchi, Philippe Froguel, Kazuyuki Tobe, Shigeo Koyasu, Kazunari Taira, Toshio Kitamura, Takao Shimizu, Ryozo Nagai, Takashi Kadowaki

Nature   423 ( 6941 ) 762 - 9   2003年06月  [査読有り]

研究論文（学術雑誌）  

Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.

Toshimasa Yamauchi, Junji Kamon, Hironori Waki, Yasushi Imai, Nobuhiro Shimozawa, Kyouji Hioki, Shoko Uchida, Yusuke Ito, Keisuke Takakuwa, Junji Matsui, Makoto Takata, Kazuhiro Eto, Yasuo Terauchi, Kajuro Komeda, Masaki Tsunoda, Koji Murakami, Yasuyuki Ohnishi, Takeshi Naitoh, Kenichi Yamamura, Yoshito Ueyama, Philippe Froguel, Satoshi Kimura, Ryozo Nagai, Takashi Kadowaki

The Journal of biological chemistry   278 ( 4 ) 2461 - 8   2003年01月  [査読有り]

研究論文（学術雑誌）  

Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.

Toshimasa Yamauchi, Junji Kamon, Yasuhiko Minokoshi, Yusuke Ito, Hironori Waki, Shoko Uchida, Shigeo Yamashita, Mitsuhiko Noda, Shunbun Kita, Kohjiro Ueki, Kazuhiro Eto, Yasuo Akanuma, Philippe Froguel, Fabienne Foufelle, Pascal Ferré, David Carling, Satoshi Kimura, Ryozo Nagai, Barbara B Kahn, Takashi Kadowaki

Nature medicine   8 ( 11 ) 1288 - 95   2002年11月  [査読有り]

研究論文（学術雑誌）  

Determination of endogenous levels of retinoic acid isomers in type II diabetes mellitus patients. Possible correlation with HbA1c values.

Yuko Yamakoshi, Hiroshi Fukasawa, Toshimasa Yamauchi, Hironori Waki, Takashi Kadowaki, Koichi Shudo, Hiroyuki Kagechi

Biological & pharmaceutical bulletin   25 ( 10 ) 1268 - 71   2002年10月  [査読有り]

研究論文（学術雑誌）  

Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene.

Kazuo Hara, Mitsuhiko Noda, Hironori Waki, Kazuyuki Tobe, Toshimasa Yamauchi, Hiroko Kadowaki, Hiroaki Satou, Kazuhisa Tsukamoto, Shinya Nagamatsu, Kazuhiro Yamagata, Yuji Matsuzawa, Yasuo Akanuma, Satoshi Kimura, Takashi Kadowaki

Internal medicine   41 ( 10 ) 848 - 52   2002年10月  [査読有り]

研究論文（学術雑誌）  

Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.

Toshimasa Yamauchi, Yuichi Oike, Junji Kamon, Hironori Waki, Kajuro Komeda, Atsuko Tsuchida, Yukari Date, Meng-Xian Li, Hiroshi Miki, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takeyori Saheki, Masamitsu Nakazato, Takeshi Naitoh, Kenichi Yamamura, Takashi Kadowaki

Nature genetics   30 ( 2 ) 221 - 6   2002年02月  [査読有り]

研究論文（学術雑誌）  

The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance.

Toshimasa Yamauchi, Junji Kamon, Hironori Waki, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Tomohiro Ide, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Hiroshi Miki, Atsuko Tsuchida, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takashi Kadowaki

The Journal of biological chemistry   276 ( 44 ) 41245 - 54   2001年11月  [査読有り]

研究論文（学術雑誌）  

Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.

Toshimasa Yamauchi, Hironori Waki, Junji Kamon, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Hiroshi Miki, Naoto Kubota, Yasuo Terauchi, Atsuko Tsuchida, Nobuyo Tsuboyama-Kasaoka, Naoko Yamauchi, Tomohiro Ide, Wataru Hori, Shigeaki Kato, Masashi Fukayama, Yasuo Akanuma, Osamu Ezaki, Akiko Itai, Ryozo Nagai, Satoshi Kimura, Kazuyuki Tobe, Hiroyuki Kagechika, Koichi Shudo, Takashi Kadowaki

The Journal of clinical investigation   108 ( 7 ) 1001 - 13   2001年10月  [査読有り]

研究論文（学術雑誌）  

The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.

Toshimasa Yamauchi, Junji Kamon, Hironori Waki, Yasuo Terauchi, Naoto Kubota, Kazuo Hara, Yasumichi Mori, Tomohiro Ide, Koji Murakami, Nobuyo Tsuboyama-Kasaoka, Osamu Ezaki, Yasuo Akanuma, Oksana Gavrilova, Charles Vinson, Marc L Reitman, Hiroyuki Kagechika, Koichi Shudo, Madoka Yoda, Yasuko Nakano, Kazuyuki Tobe, Ryozo Nagai, Satoshi Kimura, Motowo Tomita, Philippe Froguel, Takashi Kadowaki

Nature medicine   7 ( 8 ) 941 - 6   2001年08月  [査読有り]

研究論文（学術雑誌）  

Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer.

Toshimasa Yamauchi, Naoko Yamauchi, Kohjiro Ueki, Takuya Sugiyama, Hironori Waki, Hiroshi Miki, Kazuyuki Tobe, Satoru Matsuda, Toshio Tsushimai, Tadashi Yamamoto, Toshiro Fujita, Yuji Taketani, Masashi Fukayama, Satoshi Kimura, Yoshio Yazaki, Ryozo Nagai, Takashi Kadowaki

The Journal of biological chemistry   275 ( 43 ) 33937 - 44   2000年10月  [査読有り]

研究論文（学術雑誌）