Role of prostaglandin signaling in the control of glucose homeostasis

• Project/Area Number: 15K08230
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kyoto University
• Principal Investigator: YOKODE MASAYUKI 京都大学, 医学研究科, 教授 (20252447)
• Co-Investigator(Kenkyū-buntansha): 南 学 京都大学, 医学研究科, 准教授 (90511907)
• Co-Investigator(Renkei-kenkyūsha): KAMEI Kaeko 京都工芸繊維大学, 工芸科学研究科, 教授 (00214544)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プロスタグランジン / マクロファージ / 慢性炎症 / 糖代謝

Outline of Final Research Achievements

With increasing body weight, macrophages accumulate in adipose tissue, giving rise to chronic inflammation and insulin resistance. In this study, we treated db/db mice with a prostaglandin E2 type 4 receptor (EP4) -selective agonist to explore the role of EP4 signaling in obesity-related inflammation. In the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved. Administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures, but increased the number of anti-inflammatory M2 macrophages in adipose tissue. In vitro M1/M2 polarization assay showed that treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Thus, EP4 signaling plays a critical role in obesity-related adipose tissue inflammation by regulating macrophage recruitment and polarization.

Research Products

• [Journal Article] Behavioral abnormalities and reduced norepinephrine in EP4 receptor-associated protein (EPRAP)-deficient mice (2017)
  • Author(s): (3)Fujikawa R, Higuchi S, Ikedo T, Nagata M, Hayashi K, Yang T, Miyata T, Yokode M, Minami M
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 486 Issue: 2 Pages: 584-588
  • DOI: 10.1016/j.bbrc.2017.03.095
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency in EP4 Receptor?Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease (2017)
  • Author(s): Fujikawa Risako、Higuchi Sei、Nakatsuji Masato、Yasui Mika、Ikedo Taichi、Nagata Manabu、Hayashi Kosuke、Yokode Masayuki、Minami Manabu
  • Journal Title: The American Journal of Pathology Volume: 187 Issue: 8 Pages: 1848-1854
  • DOI: 10.1016/j.ajpath.2017.04.010
  • Peer Reviewed
• [Journal Article] Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation (2017)
  • Author(s): Ikedo Taichi、Minami Manabu、Kataoka Hiroharu、Hayashi Kosuke、Nagata Manabu、Fujikawa Risako、Higuchi Sei、Yasui Mika、Aoki Tomohiro、Fukuda Miyuki、Yokode Masayuki、Miyamoto Susumu
  • Journal Title: Journal of the American Heart Association Volume: 6 Issue: 6
  • DOI: 10.1161/jaha.116.004777
  • Peer Reviewed / Open Access
• [Journal Article] EP4 receptor-associated protein in microglia promotes inflammation in the brain (2016)
  • Author(s): (1)Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Masayuki Yokode, and Manabu Minami.
  • Journal Title: American Journal of Pathology Volume: 186 Issue: 8 Pages: 1982-1988
  • DOI: 10.1016/j.ajpath.2016.04.002
  • Peer Reviewed
• [Journal Article] EP4 Receptor-Associated Protein in Macrophages Protects against Bleomycin-Induced Pulmonary Inflammation in mice (2016)
  • Author(s): (2)Higuchi S, Fujikawa R, Ikedo T, Hayashi K, Yasui M, Nagata M, Nakatsuji M, Yokode M and Minami M.
  • Journal Title: The Journal of Immunology Volume: 197 Issue: 11 Pages: 4436-4443
  • DOI: 10.4049/jimmunol.1502618
  • Peer Reviewed
• [Journal Article] Safety and Anti-tumor Activity of Anti–PD-1 Antibody (Nivolumab: ONO-4538/BMS-936558) in Patients with Platinum-resistant Ovarian Cancer. (2015)
  • Author(s): Hamanishi, J., M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, T. Murayama, M. Kanai, Y. Mori, S. Matsumoto, S. Chikuma, N. Matsumura, K. Abiko, T. Baba, K. Yamaguchi, A. Ueda, Y. Hosoe, S. Morita, M. Yokode, A. Shimizu, T. Honjo, I. Konishi.
  • Journal Title: J Clin Oncol Volume: 33 Issue: 34 Pages: 4015-22
  • DOI: 10.1200/jco.2015.62.3397
  • Peer Reviewed / Open Access
• [Journal Article] The Prostaglandin E2 Receptor EP4 Regulates Obesity-related Inflammation and Insulin Sensitivity. (2015)
  • Author(s): Yasui, M., Y. Tamura, M. Minami*, S. Higuchi, R. Fujikawa, T. Ikedo, M. Nagata, H. Arai, T. Murayama, and M. Yokode.
  • Journal Title: PLoS One Volume: 10 Issue: 8 Pages: e0136304-e0136304
  • DOI: 10.1371/journal.pone.0136304
  • NAID: 120005678204
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EP4 receptor–associated protein in macrophages ameliorates colitis and colitis-associated tumorigenesis. (2015)
  • Author(s): Nakatsuji, M., M. Minami*, H. Seno*, M. Yasui, H. Komekado, S. Higuchi, R. Fujikawa, Y. Nakanishi, A. Fukuda, K. Kawada, Y. Sakai, T. Kita, P. Libby, H. Ikeuchi, M. Yokode, and T. Chiba
  • Journal Title: PLoS Genet Volume: 11 Issue: 10 Pages: e1005542-e1005542
  • DOI: 10.1371/journal.pgen.1005542
  • NAID: 120005947032
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 委員会の運用における課題と対策 (2018)
  • Author(s): 南 学
  • Organizer: 滋賀医科大学臨床研究開発センター 臨床研究法・改正指針への対応ワークショップ
• [Presentation] 抗がん剤の循環器系への副作用-Onco-Cardiologyの国内外の現状と課題 (2018)
  • Author(s): 南 学
  • Organizer: 第9回日本安全性薬理研究会学術年会
• [Presentation] 脳心血管病の包括的管理チャートの使い方(アルゴリズム) (2018)
  • Author(s): 横出 正之
  • Organizer: 日本総合健診学会 第46回大会
• [Presentation] EPRAP in microglia promotes inflammation via MKK4-mediated signaling pathway (2017)
  • Author(s): 藤川 理沙子、樋口 聖、南 学、安井 美加、池堂 太一、永田 学、横出 正之
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎、長崎市）
  • Year and Date: 2017-03-15
• [Presentation] EPRAP欠損マウスは精神疾患様の行動異常を示す (2017)
  • Author(s): 藤川 理沙子、南 学、横出 正之
  • Organizer: 第26回神経行動薬理若手研究者の集い
  • Place of Presentation: 福大メディカルホール（福岡、福岡市）
  • Year and Date: 2017-03-14
• [Presentation] Cardio-Oncologyとは (2017)
  • Author(s): 南 学
  • Organizer: 第65回日本心臓病学会
• [Presentation] Onco-Cardiologyの国内外の現状と早期診断におけるバイオマーカーの有用性 (2016)
  • Author(s): 南 学
  • Organizer: 第64回日本心臓病学会
  • Place of Presentation: 東京国際フォーラム（東京、千代田区）
  • Year and Date: 2016-09-23
• [Presentation] 膵臓マクロファージによる膵β細胞の慢性炎症におけるEP4シグナルの役割 (2015)
  • Author(s): 安井 美加, 南 学, 橫出 正之
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会合同大会（BMB2015）
  • Place of Presentation: 神戸（兵庫）
  • Year and Date: 2015-12-01
• [Presentation] EP4受容体活性化による2型糖尿病マウスのインスリン抵抗性改善機構 (2015)
  • Author(s): 安井 美加, 南 学, 橫出 正之
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関（山口）
  • Year and Date: 2015-05-21