Elucidation of the molecular basis of the diseases caused by abnormalities in networks of energy metabolism

• Project/Area Number: 18KT0017
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Keio University (2021); The University of Tokyo (2018-2020)
• Principal Investigator: Tanaka Hirotoshi 慶應義塾大学, 医学部(信濃町), 特別招聘教授 (00171794)
• Co-Investigator(Kenkyū-buntansha): 井元 清哉 東京大学, 医科学研究所, 教授 (10345027)
• Project Period (FY): 2018-07-18 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2020: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
• Keywords: 複雑系 / 代謝 / グルココルチコイド受容体 / 臓器連関 / 肥満 / サルコペニア / 骨格筋 / 性差 / 代謝学 / 内分泌学 / オミクス / 生活習慣病 / 糖尿病 / 数理科学 / エネルギー代謝 / 多臓器連関 / グルココルチコイド / 遺伝子発現 / 体組成 / 情報科学

Outline of Final Research Achievements

The systemic energy metabolism and body composition are controlled by many factors and regulatory systems, and the manner varies depending on the individual's condition. We considered that such a complex metabolic system is also important in the pathophysiology of obesity, diabetes, and sarcopenia. In this study, we conducted mathematical analyses and molecular biological verification in multiple metabolic model mice. The first of our findings is that excessive fat accumulation in obesity is partly via glucocorticoid signaling in skeletal muscle and related hyperinsulinemia. Second, age-associated early sarcopenic changes involved muscle weakness, and a nutritional intervention that regulates individual's metabolism effectively prevented it. Third, sex differences are found in such mechanisms in muscle-regulated fat accumulation and age-associated early sarcopenic changes.

Academic Significance and Societal Importance of the Research Achievements

肥満や加齢のマウスモデルの解析を通じて、個体の代謝システムの規則性を創る本質的な因子の同定が進むとともに、代謝システムが状況に応じて変容すること、個体背景によって異なること、についての理解が進んだ。本研究で志向した複雑系解析と分子生物学の融合という手法の有用性も明らかとなった。エネルギー代謝に関わる各種の病態（肥満、加齢、糖尿病、脂肪肝、筋萎縮など）の新しい予防法および治療法の開発、とくに個別化医療の実現にも貢献する知見が得られたと考えられる。

Research Products

• [Journal Article] The differential diagnosis of IgG4-related disease based on machine learning. (2022)
  • Author(s): Motohisa Yamamoto, Hiroki Yamazaki, Hirotoshi Tanaka, et al.
  • Journal Title: Arthritis Res Ther. Volume: 24 Issue: 1 Pages: 71-71
  • DOI: 10.1186/s13075-022-02752-7
  • Peer Reviewed / Open Access
• [Journal Article] Aseptic Meningitis-retention Syndrome Associated with Tocilizumab in a Patient with Idiopathic Multicentric Castleman Disease (2021)
  • Author(s): Akira Arakawa, Masaki Iizuka, Shunichi Matsuda, Erika Matsubara, Hiroki Yamazaki, Noritada Yoshikawa, Hirotoshi Tanaka, Toshihiro Yoshizawa.
  • Journal Title: Internal Medicine Volume: 60 Issue: 24 Pages: 3995-3998
  • DOI: 10.2169/internalmedicine.6938-20
  • NAID: 130008129490
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-12-15
  • Peer Reviewed / Open Access
• [Journal Article] Glycyrrhizin Derivatives Suppress Cancer Chemoresistance by Inhibiting Progesterone Receptor Membrane Component 1 (2021)
  • Author(s): Yasuaki Kabe, Ikko Koike, Tatsuya Yamamoto, Miwa Hirai, Ayaka Kanai, Ryogo Furuhata, Hitoshi Tsugawa, Erisa Harada, Kenji Sugase, Kazue Hanadate, Nobuji Yoshikawa, Hiroaki Hayashi, Masanori Noda, Susumu Uchiyama, Hiroki Yamazaki, Hirotoshi Tanaka, Takuya Kobayashi, Hiroshi Handa, Makoto Suematsu.
  • Journal Title: Cancers (Basel) Volume: 13 Issue: 13 Pages: 3265-3265
  • DOI: 10.3390/cancers13133265
  • Peer Reviewed / Open Access
• [Journal Article] The Influence of Glucocorticoid Receptor on Sex Differences of Gene Expression Profile in Skeletal Muscle (2021)
  • Author(s): Yoshikawa Noritada、Oda Aya、Yamazaki Hiroki、Yamamoto Motohisa、Kuribara-Souta Akiko、Uehara Masaaki、Tanaka Hirotoshi
  • Journal Title: Endocrine Research Volume: - Issue: 3 Pages: 1-15
  • DOI: 10.1080/07435800.2021.1884874
  • Peer Reviewed / Open Access
• [Journal Article] Eicosapentaenoic acid changes muscle transcriptome and intervenes in aging-related fiber type transition in male mice (2021)
  • Author(s): Yamazaki Hiroki、Nishimura Mayu、Uehara Masaaki、Kuribara-Souta Akiko、Yamamoto Motohisa、Yoshikawa Noritada、Morohashi Ken-Ichirou、Tanaka Hirotoshi
  • Journal Title: American Journal of Physiology-Endocrinology and Metabolism Volume: 320 Issue: 2 Pages: E346-E358
  • DOI: 10.1152/ajpendo.00184.2020
  • Peer Reviewed / Open Access
• [Journal Article] Correlation among body composition and metabolic regulation in a male mouse model of Cushing’s syndrome (2020)
  • Author(s): Uehara M, Yamazaki H, Yoshikawa N, Kuribara-Souta A, Tanaka H
  • Journal Title: Endocrine Journal Volume: 67 Issue: 1 Pages: 21-30
  • DOI: 10.1507/endocrj.EJ19-0205
  • NAID: 130007790982
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes (2020)
  • Author(s): Furuhata Ryogo、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Tsugawa Hitoshi、Sugiyama Eiji、Hirai Miwa、Yamamoto Takehiro、Koike Ikko、Yoshikawa Noritada、Tanaka Hirotoshi、Koseki Masahiro、Nakae Jun、Matsumoto Morio、Nakamura Masaya、Suematsu Makoto
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 479-479
  • DOI: 10.1038/s42003-020-01202-x
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease. (2020)
  • Author(s): Yabe H, Kamekura R, Yamamoto M, Murayama K, Kamiya S, Ikegami I, Shigehara K, Takaki H, Chiba H, Takahashi H, Takano K, Takahashi H, Ichimiya S.
  • Journal Title: Mod Rheumatol. Volume: Feb 5 Issue: 1 Pages: 1-12
  • DOI: 10.1080/14397595.2020.1719576
  • Peer Reviewed / Open Access
• [Journal Article] Differences in clinical features of IgG4-related disease between elderly and younger patients (2019)
  • Author(s): Yamamoto M, Takahashi H, Tanaka H
  • Journal Title: Geriatr Gerontol Int Volume: 19 Issue: 6 Pages: 564-565
  • DOI: 10.1111/ggi.13662
  • Peer Reviewed / Open Access
• [Journal Article] GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells (2019)
  • Author(s): Zentaro Kiuchi, Yukino Nishibori, Satoru Kutsuna, et al.
  • Journal Title: FASEB J Volume: 33 Issue: 6 Pages: 7387-7402
  • DOI: 10.1096/fj.201800344rr
  • Peer Reviewed / Open Access
• [Journal Article] Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy (2019)
  • Author(s): Matsuhashi Tomohiro、Endo Jin、Katsumata Yoshinori、Yamamoto Tsunehisa、Shimizu Noriaki、Yoshikawa Noritada、Kataoka Masaharu、Isobe Sarasa、Moriyama Hidenori、Goto Shinichi、Fukuda Keiichi、Tanaka Hirotoshi、Sano Motoaki
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 130 Pages: 122-130
  • DOI: 10.1016/j.yjmcc.2019.03.019
  • Peer Reviewed / Open Access
• [Journal Article] Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages (2018)
  • Author(s): Yamazaki Hiroki、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Yamamotoya Takeshi、Nakatsu Yusuke、Kikuchi Takako、Kaneko Sunao、Tanaka Hirotoshi、Asano Tomoichiro
  • Journal Title: Mediators of Inflammation Volume: 2018 Pages: 1-12
  • DOI: 10.1155/2018/3062319
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation (2018)
  • Author(s): K. Anan, S. Hino, N. Shimizu, A. Sakamoto, K. Nagaoka, R. Takase, K. Kohrogi, H. Araki, Y. Hino, S. Usuki, S. Oki, H. Tanaka, K. Nakamura, F. Endo, and M. Nakao
  • Journal Title: Nucleic Acids Res. Volume: 18 Issue: 11 Pages: 5441-5454
  • DOI: 10.1093/nar/gky234
  • Peer Reviewed / Open Access
• [Journal Article] Effects of long-term intake of a yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 on mice (2018)
  • Author(s): Usui Yuki、Kimura Yasumasa、Satoh Takeshi、Takemura Naoki、Ouchi Yasuo、Ohmiya Hiroko、Kobayashi Kyosuke、Suzuki Hiromi、Koyama Satomi、Hagiwara Satoko、Tanaka Hirotoshi、Imoto Seiya、Eberl G?rard、Asami Yukio、Fujimoto Kosuke、Uematsu Satoshi
  • Journal Title: International Immunology Volume: 30 Issue: 7 Pages: 319-331
  • DOI: 10.1093/intimm/dxy035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effects of acute aerobic exercise on the lipid profiles in transgender men (2022)
  • Author(s): Mizuki Yamada, Nodoka Ikegami, Hyunjun Gam, Yuriko Nishikawa, Akira Ishikawa, Akiko Funaki, Kayoko Kamemoto, Tomoka Matsuda, Hazuki Ogata, Hirotoshi Tanaka, Hiroki Yamazaki, Mikako Sakamaki-Sunaga
  • Organizer: American College of Sports Medicine 69th Annual Meeting
  • Int'l Joint Research
• [Presentation] グルココルチコイドとサルコペニア (2022)
  • Author(s): 田中廣壽、山崎広貴
  • Organizer: 第95回日本内分泌学会学術総会
  • Invited
• [Presentation] 肥満の病態における骨格筋グルココルチコイド受容体シグナルの役割 (2021)
  • Author(s): 山崎広貴、上原昌晃、栗原明子、山本元久、平川泰子、加部泰明、末松誠、田中廣壽
  • Organizer: 第７回日本筋学学術集会
• [Presentation] 機械学習に基づくIgG4関連疾患の診断支援の試み (2021)
  • Author(s): 山本元久、上原昌晃、山崎広貴、吉川賢忠、水島伊知郎、庄田宏文、吉藤元、川野充弘、高橋裕樹、藤尾圭志、田中廣壽
  • Organizer: 第65回日本リウマチ学会学術集会
• [Presentation] 一過性有酸素運動がFTMの動脈スティフネスに与える影響 (2021)
  • Author(s): 山田満月、池上和、甘賢俊、西川百合子、石川明良、舟喜晶子、亀本佳世子、松田知華、緒方はづき、田中廣壽、山崎広貴、須永美歌子
  • Organizer: 第76回日本体力医学会大会
• [Presentation] 骨格筋と多(他)臓器連関 (2020)
  • Author(s): 田中廣壽
  • Organizer: 第41回日本炎症再生医学会
  • Invited
• [Presentation] ステロイドホルモンの新たな作用 (2020)
  • Author(s): 田中廣壽
  • Organizer: 第93回日本内分泌学会学術総会
  • Invited
• [Presentation] 特別講演「ステロイドのエッセンス」 (2019)
  • Author(s): 田中 廣壽
  • Organizer: 第30回日本リウマチ学会中国・四国支部学術集会
  • Invited
• [Presentation] 骨格筋サイエンスの新展開 (2019)
  • Author(s): 田中 廣壽
  • Organizer: 第37回日本骨代謝学会学術集会
  • Invited
• [Presentation] Glucocorticoid receptor today (2019)
  • Author(s): 田中 廣壽
  • Organizer: The Fifth Symposium of the Korean Adrenal Gland and Endocrine Hypertension Study Group
  • Int'l Joint Research / Invited
• [Presentation] Novel aspects of glucocorticoid receptor in physiology; Lessons from skeletal muscle and heart (2019)
  • Author(s): 田中 廣壽
  • Organizer: the Steroid Today 2019
  • Int'l Joint Research / Invited
• [Presentation] リウマチ膠原病臨床と骨格筋のサイエンス (2019)
  • Author(s): 田中 廣壽
  • Organizer: RA治療セミナー
  • Invited
• [Presentation] 免疫代謝内分泌に関わる臓器連関 (2018)
  • Author(s): 田中 廣壽
  • Organizer: 免疫・代謝・内分泌アカデミアフォーラム2018
  • Invited
• [Presentation] Skeletal muscle glucocorticoid receptor and systemic energy metabolism (2018)
  • Author(s): 田中 廣壽
  • Organizer: 4th Congress on Steroid Research 2018
  • Int'l Joint Research / Invited
• [Presentation] ステロイドによる筋萎縮の分子機構解明と臨床への橋渡し、そして骨格筋の新しい役割の解明へ (2018)
  • Author(s): 田中 廣壽
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 骨格筋と肥満 (2018)
  • Author(s): 田中 廣壽
  • Organizer: 第16回肥満症カンファレンス
  • Invited
• [Remarks] 研究紹介
  • URL: https://www.ims.u-tokyo.ac.jp/Rheumatol/allergy/research.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/Rheumatol/allergy/research.html