M2 macrophages as a novel therapeutic target in high-fat diet-induced cardiomyopathy

• Project/Area Number: 18K08505
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: University of Toyama
• Principal Investigator: Yagi Kunimasa 富山大学, 学術研究部医学系, 准教授 (30293343)
• Co-Investigator(Kenkyū-buntansha): 戸辺 一之 富山大学, 学術研究部医学系, 教授 (30251242)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: CD206 / 心筋症 / 繊維化 / M2マクロファージ / 肥満心筋症 / 慢性心不全 / 心不全 / 糖尿病

Outline of Final Research Achievements

We have found that mice genetically deficient in CD206, a marker of M2 macrophages, could be a cardiomyopathy model. The relationship between macrophages and heart failure has been discussed only with inflammation and damage repair, including myocarditis. Our results showed cardiac hypertrophy, increased expression of BNP, and myocardial fibrosis-related genes in MRI, echocardiography, and tissue. Although CD206 is expressed in the myocardium, tissue macrophages in the myocardium were confirmed to affect by CD206 KO. Furthermore, myocardial hypertrophy was more pronounced in the regular diet than in the high-fat diet. Thus, loss or decreased expression of CD206 leads to myocardial hypertrophy through myocardial fibrosis.

Academic Significance and Societal Importance of the Research Achievements

学術的意義の第一としては、従来サルコメア蛋白の異常による心筋症モデルしか存在していなかった所で、M2マクロファージのマーカーであるCD206をノックアウトしたり欠損したりしたモデルが心筋繊維化を促進させBNP上昇を示す心筋症類似病態を呈するということが明らかとなったことが挙げられる。当初の推測とは逆で、高脂肪食と正常食では、むしろ正常食で心筋肥大が顕著であったことも興味深い。本モデルの検討を進めることにより、特に生活習慣病を背景とする心筋拡張障害の病態の解明や新規治療の可能性が広がることが期待される。

Research Products

• [Journal Article] Type 1 diabetes woman with repeated miscarriages successfully gave birth after introducing an insulin pump with a predictive low glucose suspend feature (2021)
  • Author(s): Honoki Hisae、Yagi Kunimasa、Tsuda Sayaka、Wada Tsutomu、Enkaku Asako、Nakagawa-Yokoyama Maki、Kamigishi Miki、Shikata Masataka、Takikawa-Nishiday Akiko、Fujisaka Shiho、Chujo Daisuke、Sasaoka Toshiyasu、Nakashima Akitoshi、Saito Shigeru、Tobe Kazuyuki
  • Journal Title: Diabetology International Volume: 12 Issue: 3 Pages: 324-329
  • DOI: 10.1007/s13340-020-00489-9
  • NAID: 40022593484
  • Peer Reviewed / Open Access
• [Journal Article] Diastolic Cardiac Function Improvement by Liraglutide Is Mainly Body Weight Reduction Dependent but Independently Contributes to B-Type Natriuretic Peptide Reduction in Patients with Type 2 Diabetes with Preserved Ejection Fraction (2021)
  • Author(s): Yagi Kunimasa、Imamura Teruhiko、Tada Hayato、Chujo Daisuke、Liu Jianhui、Shima Yuuki、Ohbatake Azusa、Miyamoto Yukiko、Okazaki Satoko、Ito Naoko、Nakano Kaoru、Shikata Masataka、Enkaku Asako、Takikawa Akiko、Honoki Hisae、Fujisaka Shiho、Origasa Hideki、Tobe Kazuyuki
  • Journal Title: Journal of Diabetes Research Volume: 2021 Pages: 1-10
  • DOI: 10.1155/2021/8838026
  • Peer Reviewed / Open Access
• [Journal Article] Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue (2021)
  • Author(s): Kuwano Takahide, Izumi Hironori, Aslam Muhammad Rahil, Igarashi Yoshiko, Bilal Muhammad, Nishimura Ayumi, Watanabe Yoshiyuki, Nawaz Allah, Kado Tomonobu, Ikuta Koichi, Yamamoto Seiji, Sasahara Masakiyo, Fujisaka Shiho, Yagi Kunimasa, Mori Hisashi, Tobe Kazuyuki
  • Journal Title: PLOS ONE Volume: 16 Issue: 3 Pages: e0248267-e0248267
  • DOI: 10.1371/journal.pone.0248267
  • Peer Reviewed / Open Access
• [Journal Article] Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway (2020)
  • Author(s): Nishida Yasuhiro、Nawaz Allah、Kado Tomonobu、Takikawa Akiko、Igarashi Yoshiko、Onogi Yasuhiro、Wada Tsutomu、Sasaoka Toshiyasu、Yamamoto Seiji、Sasahara Masakiyo、Imura Johji、Tokuyama Kumpei、Usui Isao、Nakagawa Takashi、Fujisaka Shiho、Kunimasa Yagi、Tobe Kazuyuki
  • Journal Title: Journal of Cachexia, Sarcopenia and Muscle Volume: 11 Issue: 1 Pages: 241-258
  • DOI: 10.1002/jcsm.12530
  • Peer Reviewed / Open Access
• [Journal Article] Bofutsushosan improves gut barrier function with a bloom of Akkermansia muciniphila and improves glucose metabolism in mice with diet-induced obesity (2020)
  • Author(s): Fujisaka Shiho、Usui Isao、Nawaz Allah、Igarashi Yoshiko、Okabe Keisuke、Furusawa Yukihiro、Watanabe Shiro、Yamamoto Seiji、Sasahara Masakiyo、Watanabe Yoshiyuki、Nagai Yoshinori、Yagi Kunimasa、Nakagawa Takashi、Tobe Kazuyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5544-5544
  • DOI: 10.1038/s41598-020-62506-w
  • Peer Reviewed / Open Access
• [Journal Article] Family history of diabetes in both parents is strongly associated with impaired residual β-cell function in Japanese type 2 diabetes patients (2020)
  • Author(s): Iwata Minoru, Kamura Yutaka, Honoki Hisae, Kobayashi Kaori, Ishiki Manabu, Yagi Kunimasa, Fukushima Yasuo, Takano Atsuko, Kato Hiromi, Murakami Shihou, Higuchi Kiyohiro, Kobashi Chikaaki, Fukuda Kazuhito, Koshimizu Yukiko, Tobe Kazuyuki
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Issue: 3 Pages: 564-572
  • DOI: 10.1111/jdi.13176
  • Peer Reviewed / Open Access
• [Journal Article] One Single Nucleotide Polymorphism of the TRPM2 Channel Gene Identified as a Risk Factor in Bipolar Disorder Associates With Autism Spectrum Disorder in a Japanese Population (2020)
  • Author(s): Mahmuda Naila Al、Yokoyama Shigeru、Munesue Toshio、Hayashi Kenshi、Yagi Kunimasa、Tsuji Chiharu、Higashida Haruhiro
  • Journal Title: Diseases Volume: 8 Issue: 1 Pages: 4-4
  • DOI: 10.3390/diseases8010004
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells Among the 3 Subtypes of Type 1 Diabetes (2020)
  • Author(s): Chujo Daisuke, Kawabe Akitsu, Matsushita Maya, Takahashi Nobuyuki, Tsutsumi Chiharu, Haseda Fumitaka, Imagawa Akihisa, Hanafusa Toshiaki, Ueki Kohjiro, Kajio Hiroshi, Yagi Kunimasa, Tobe Kazuyuki, Shimoda Masayuki
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 105 Issue: 10 Pages: 3141-3151
  • DOI: 10.1210/clinem/dgaa447
  • Peer Reviewed / Open Access
• [Journal Article] A proposal of evaluation method using a pressure sensor for supporting auscultation training (2020)
  • Author(s): Kodera Yuki、Yagi Kunimasa、Shikida Mikifumi
  • Journal Title: 15th International Joint Symposium on Artificial Intelligence and Natural Language Processing (iSAI-NLP), Volume: 2020 Pages: 267-272
  • DOI: 10.1109/isai-nlp51646.2020.9376779
  • Peer Reviewed / Open Access
• [Journal Article] High prevalence of fragmented QRS on electrocardiography in Japanese subjects with diabetes irrespective of metabolic syndrome (2020)
  • Author(s): Yagi Kunimasa、Nagata Yoshiki、Yamagami Takashi、Kamigishi Miki、Yokoyama Maki Nakagawa、Shikata Masataka、Enkaku Asako、Nishida Akiko Takikawa、Honoki Hisae、Fujisaka Shiho、Chujo Daisuke、Origasa Hideki、Tobe Kazuyuki
  • Journal Title: Journal of Diabetes Investigation Volume: 12 Pages: 1680-1688
  • DOI: 10.21203/rs.3.rs-123784/v1
  • Peer Reviewed / Open Access
• [Journal Article] Anti-programmed death ligand 1 therapy-induced type 1 diabetes presenting with multiple islet-related autoantibodies (2020)
  • Author(s): Honoki Hisae, Yagi Kunimasa, Kambara Kenta, Chujo Daisuke, Shikata Masataka, Enkaku Asako, Takikawa-Nishida Akiko, Liu Jianhui, Fujisaka Shiho, Tobe Kazuyuki
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Issue: 1 Pages: 253-254
  • DOI: 10.1111/jdi.13099
  • Peer Reviewed / Open Access
• [Journal Article] Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of <i>HNF1B</i> based on 17q12 microdeletion (2019)
  • Author(s): Omura Yoshiyuki、Yagi Kunimasa、Honoki Hisae、Iwata Minoru、Enkaku Asako、Takikawa Akiko、Kuwano Takahide、Watanabe Yoshiyuki、Nishimura Ayumi、Liu Jianhui、Chujo Daisuke、Fujisaka Shiho、Enya Mayumi、Horikawa Yukio、Tobe Kazuyuki
  • Journal Title: Endocrine Journal Volume: 66 Issue: 12 Pages: 1113-1116
  • DOI: 10.1507/endocrj.EJ19-0020
  • NAID: 130007772410
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophage‐specific hypoxia‐inducible factor‐1α deletion suppresses the development of liver tumors in high‐fat diet‐fed obese and diabetic mice (2019)
  • Author(s): Takikawa Akiko、Usui Isao、Fujisaka Shiho、Tsuneyama Koichi、Okabe Keisuke、Nakagawa Takashi、Nawaz Allah、Kado Tomonobu、Jojima Teruo、Aso Yoshimasa、Hayakawa Yoshihiro、Yagi Kunikimi、Tobe Kazuyuki
  • Journal Title: Journal of Diabetes Investigation Volume: in press Issue: 6 Pages: 1-8
  • DOI: 10.1111/jdi.13047
  • NAID: 120006980551
  • Peer Reviewed / Open Access
• [Journal Article] The relationship between patients’ perception of type 2 diabetes and medication adherence: a cross-sectional study in Japan (2019)
  • Author(s): Kana Hashimoto†, Koki Urata†, Ayano Yoshida, Reiko Horiuchi, Naoto Yamaaki, Kunimasa Yagi and Kunizo Arai
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 5 Issue: 1 Pages: 1-10
  • DOI: 10.1186/s40780-019-0132-8
  • Peer Reviewed / Open Access
• [Journal Article] Clinical whole exome sequencing in severe hypertriglyceridemia (2019)
  • Author(s): Tada Hayato、Nomura Akihiro、Okada Hirofumi、Nakahashi Takuya、Nozue Tsuyoshi、Hayashi Kenshi、Nohara Atsushi、Yagi Kunimasa、Inazu Akihiro、Michishita Ichiro、Mabuchi Hiroshi、Yamagishi Masakazu、Kawashiri Masa-aki
  • Journal Title: Clinica Chimica Acta Volume: 488 Pages: 31-39
  • DOI: 10.1016/j.cca.2018.10.041
  • Peer Reviewed / Open Access
• [Journal Article] C-Peptide Area Under the Curve at Glucagon Stimulation Test Predicts Glucose Improvements by GLP-1 Receptor Analogue: A Retrospective Observational Study (2019)
  • Author(s): Ohbatake A, Yagi K, Karashima S, Shima Y, Miyamoto Y, Asaka H, Okazaki S, Kometani M, Kawashiri MA, Takeda Y, Yoneda T, Chujo D.
  • Journal Title: Diabetes Ther Volume: 10 Issue: 2 Pages: 673-681
  • DOI: 10.1007/s13300-019-0586-6
  • Peer Reviewed / Open Access
• [Journal Article] A Method for Supporting Medical-interview Training using Smart Devices (2019)
  • Author(s): Shikida Mikifumi、Kodera Yuki、Inoue Shunya、Yagi Kunimasa
  • Journal Title: IEEE Knowledge, Information and Creativity Support Systems (KICSS) Volume: 20190109 Pages: 1-6
  • DOI: 10.1109/kicss45055.2018.8950557
  • Peer Reviewed / Open Access
• [Journal Article] Ratio of low molecular weight serum adiponectin to the total adiponectin value is associated with type 2 diabetes through its relation to increasing insulin resistance. (2018)
  • Author(s): Iwata M, Hara K, Kamura Y, Honoki H, Fujisaka S, Ishiki M, Usui I, Yagi K, Fukushima Y, Takano A, Kato H, Murakami S, Higuchi K, Kobashi C, Fukuda K, Koshimizu Y, Tobe K.
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0192609-e0192609
  • DOI: 10.1371/journal.pone.0192609
  • Peer Reviewed / Open Access
• [Journal Article] High frequency of type 2 diabetes and impaired glucose tolerance in Japanese subjects with the angiopoietin-like protein 8 R59W variant. (2018)
  • Author(s): Liu J, Yagi K, Nohara A, Chujo D, Ohbatake A, Fujimoto A, Miyamoto Y, Kobayashi J, Yamagishi M.
  • Journal Title: J Clin Lipidol Volume: 12 Issue: 2 Pages: 331-337
  • DOI: 10.1016/j.jacl.2017.12.011
  • Peer Reviewed / Open Access
• [Journal Article] Effect of sodium glucose cotransporter 2 inhibitors on obstructive sleep apnea in patients with type 2 diabetes (2018)
  • Author(s): Sawada Kei、Karashima Shigehiro、Kometani Mitsuhiro、Oka Rie、Takeda Yoshimichi、Sawamura Toshitaka、Fujimoto Aya、Demura Masashi、Wakayama Ayako、Usukura Mikiya、Yagi Kunimasa、Takeda Yoshiyu、Yoneda Takashi
  • Journal Title: Endocrine Journal Volume: 65 Issue: 4 Pages: 461-467
  • DOI: 10.1507/endocrj.EJ17-0440
  • NAID: 130006727071
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sirt1 activator induces proangiogenic genes in preadipocytes to rescue insulin resistance in diet-induced obese mice (2018)
  • Author(s): Nawaz Allah、Mehmood Arshad、Kanatani Yukiko、Kado Tomonobu、Igarashi Yoshiko、Takikawa Akiko、Yamamoto Seiji、Okabe Keisuke、Nakagawa Takashi、Yagi Kunimasa、Fujisaka Shiho、Tobe Kazuyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11370-11370
  • DOI: 10.1038/s41598-018-29773-0
  • Peer Reviewed / Open Access
• [Presentation] 教育講演：足病変 (2020)
  • Author(s): 八木邦公
  • Organizer: 第54回糖尿病学の進歩
  • Invited
• [Presentation] 教育講演：心不全 (2020)
  • Author(s): 八木邦公
  • Organizer: 第35回日本糖尿病合併症学会
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• [Presentation] 入院を契機に減量・代謝改善した高度肥満症の一例 (2019)
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  • Organizer: 第116回日本内科学会総会
• [Presentation] 合併症を持つ高齢者に対する薬物療法のポイン ト (2019)
  • Author(s): 八木邦公
  • Organizer: 第34回日本糖尿病合併症学会・第25回日本糖尿病眼学会総会
  • Invited
• [Presentation] MELAS3243 変異を有する糖尿病 7 症例の剖検臓器の変異率の検討. (2018)
  • Author(s): 八木邦公，岡崎智子，大畠 梓，劉 建輝，朴木久恵，藤坂志帆，小堀健一，莇 也寸志，袖本幸男，戸邉一之.
  • Organizer: 第 91 回日本内分泌学会学術総会
• [Presentation] 発症 24 年後にカベルゴリンを投与し血糖コントロールが良好となった末端肥大症の 1 例 (2018)
  • Author(s): 朴木久恵，岩田 実，上野麻子，渡邊善之，中嶋 歩，岡部圭介，角 朝信，瀧川章子，藤坂志帆，石木 学，八 木邦公，戸邉一之
  • Organizer: 第 91 回日本内分泌学会学術総会
• [Presentation] 防風通聖散は腸内 細菌 Akkermansia muciniphila を増加させ、高脂肪食負荷マウスの糖代謝を改善する (2018)
  • Author(s): 藤坂志帆，薄井 勲，ナワズアラー，五十嵐喜子，角 朝信，古澤之裕，八木邦公，戸邉一之
  • Organizer: 第 91 回日本内分泌学会学術総会
• [Presentation] 無症候性の褐色細胞腫の一例 (2018)
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  • Organizer: 第 91 回日本内分泌学会学術総会
• [Presentation] Depletion of CD206 M2 macophages promoters browning of white adipose tissue (2018)
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  • Organizer: 第28回 臨床内分泌代謝 Update