Establishment of research fundation of IRF7 on the treatment of obesity and metabolic syndrome

• Project/Area Number: 16K09753
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokushima
• Principal Investigator: SAKAUE Hiroshi 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (60372645)
• Research Collaborator: KURODA masashi ; TSUTSUMI rie
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 脂肪細胞 / 肥満 / メタボリックシンドローム / 転写因子 / IRF7 / ベージュ脂肪細胞 / UCP-1 / MCP-1 / 2型糖尿病 / 糖尿病

Outline of Final Research Achievements

Through the combination of DNA microarray and genomic data analysis to predict DNA binding motif, we have identified the transcription factor, Interferon Regulatory Factor 7 (IRF7) as a possible regulator of the genes related to adipocyte hypertrophy. To clarify the role of IRF7 in adipocytes, we found that enforced expression of IRF7 induced the transcription of Monocyte Chemoattractant Proteoin-1 (MCP-1), a key initial adipokine in chronic inflammation in obesity. CRISPR/Cas9 mediated-suppression of IRF7 leaded to significant reduction of MCP-1 mRNA. Luciferase assay and ChIP-PCR analysis shows that IRF7 transactivates MCP-1 gene. Taken together, our results suggest that IRF7 trans-activates MCP-1 mRNA in adipocyte, and might be involved in adipose tissue inflammation associated with obesity.

Academic Significance and Societal Importance of the Research Achievements

肥満形成とその病態発症機構における転写因子IRF7の役割が解明できうるとできたと考えられ、IRF7を分子標的とした新しい肥満・メタボリックシンドローム治療への意義を確立しえた。さらにTLR9-IRF7パスウエイを阻害する小分子化合物や薬剤の探索への基礎的基盤が確立した。TLR9-IRF7パスウエイを活性化するリガンド（DNAなど）を探索し、肥満モデルマウスに対して、受容体阻害薬の効果を検討することで、肥満とそれに伴う生活習慣病の治療に新たなアイデアが提供できたことからも、その社会的意義は大きい。

Research Products

• [Journal Article] Role of orexin in exercise-induced leptin sensitivity in the mediobasal hypothalamus of mice. (2019)
  • Author(s): Shiuchi T, Miyatake Y, Otsuka A, Chikahisa S, Sakaue H
  • Journal Title: Biochem Biophys Res Commun. Volume: 514 Pages: 166-172
  • NAID: 120006881396
  • Peer Reviewed
• [Journal Article] ADCY3遺伝子異常と肥満 (2019)
  • Author(s): 黒田 雅士 三島 優奈, 阪上 浩
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 48 Pages: 214-218
  • NAID: 40021856391
• [Journal Article] Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolism. (2018)
  • Author(s): Chikugo M, Sebe M, Tsutsumi R, Iuchi M, KIshi J, Kuroda M, Harada N, Nishioka Y, Sakaue H
  • Journal Title: J Med Invest. Volume: 65 Pages: 166-170
  • NAID: 130007495818
  • Peer Reviewed / Open Access
• [Journal Article] Readthrough of ACTN3 577X nonsense mutation produces full-length α-actinin-3 protein. (2018)
  • Author(s): Harada N, Hatakeyama A, Okuyama M, Miyatake Y, Nakagawa T, Kuroda M, Masumoto S, Tsutsumi R, Nakaya Y, Sakaue H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 502 Pages: 422-428
  • Peer Reviewed
• [Journal Article] Adipocyte Death and Chronic Inflammation in Obesity. (2017)
  • Author(s): Kuroda M, Sakaue H.
  • Journal Title: J Med Invest. Volume: 64 Pages: 193-196
  • NAID: 130006105191
  • Peer Reviewed / Open Access
• [Journal Article] Cell-cycle arrest in mature adipocytes impairs BAT development but not WAT browning, and reduces adaptive thermogenesis in mice (2017)
  • Author(s): Okamatsu-Ogura Yuko、Fukano Keigo、Tsubota Ayumi、Nio-Kobayashi Junko、Nakamura Kyoko、Morimatsu Masami、Sakaue Hiroshi、Saito Masayuki、Kimura Kazuhiro
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 6648-6648
  • DOI: 10.1038/s41598-017-07206-8
  • NAID: 120006482570
  • Peer Reviewed / Open Access
• [Journal Article] Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice. (2017)
  • Author(s): Miyake M, Kuroda M, Kiyonari H, Takehana K, Hisanaga S, Morimoto M, Zhang J, Oyadomari M, Sakaue H, Oyadomari S.
  • Journal Title: PLoS One. Volume: 12 Issue: 6 Pages: e0179955-e0179955
  • DOI: 10.1371/journal.pone.0179955
  • NAID: 120006812009
  • Peer Reviewed / Open Access
• [Journal Article] Endoplasmic reticulum stress in mice increases hepatic expression of genes carrying a premature termination codon via a nutritional status-independent GRP78-dependent mechanism. (2017)
  • Author(s): Harada N, Okuyama M, Yoshikatsu A, Yamamoto H, Ishiwata S, Hamada C, Hirose T, Shono M, Kuroda M, Tsutsumi R, Takeo J, Taketani Y, Nakaya I, Sakaue H.
  • Journal Title: J Cell Biochem Volume: 印刷中 Issue: 11 Pages: 3810-3824
  • DOI: 10.1002/jcb.26031
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Heparin Cofactor Ⅱ in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice (2017)
  • Author(s): Kurahashi K, Inoue S, Yoshida S, Ikeda Y, Morimoto K, Uemoto R, Ishikawa K, Kondo T, Yuasa T, Endo I, Miyake M, Oyadomari S, Matsumoto T, Abe M, Sakaue H, Aihara KI.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 12 Pages: 1215-1230
  • DOI: 10.5551/jat.37739
  • NAID: 130006235273
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] A novel lipoprotein (a) lowering drug, D-47, decreases neointima thickening after vascular injury (2017)
  • Author(s): Nakaya Y, Fukuda D, Oyamada T, Ogawa K, Harada N, Nakagami H, Morishita R, Sata M, Sakaue, H.
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 1.2 Pages: 64-67
  • DOI: 10.2152/jmi.64.64
  • NAID: 130005501982
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Intracerebroventricular injection of ghrelin decreases wheel running activity in rats. (2016)
  • Author(s): Miyatake Y, Shiuchi T, Mawatari K, Toda S, Taniguchi Y, Futami A, Sato F, Kuroda M, Sebe M, Tsutsumi R, Harada N, Minokoshi Y, Kitamura T, Gotoh K, Ueno M, Nakaya Y, Sakaue H.
  • Journal Title: Peptide Volume: 87 Pages: 12-19
  • DOI: 10.1016/j.peptides.2016.11.005
  • Peer Reviewed / Open Access
• [Journal Article] Long-chain monounsaturated fatty acid-rich fish oil attenuates the development of atherosclerosis in mouse models. (2016)
  • Author(s): Yang ZH, Bando M, Sakurai T, Chen Y, Emma-Okon B, Wilhite B, Fukuda D, Pryor BV, Wakabayashi Y, Sampson M, Yu ZX, Sakurai A, Zarzour A, Miyahara H, Takeo J, Sakaue H, Sata M, Remaley AT.
  • Journal Title: Molecular Nutrition & Food Research Volume: 60 Issue: 10 Pages: 2208-2218
  • DOI: 10.1002/mnfr.201600142
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Depot- and gender-specific expression of NLRP3 inflammasome and toll-like receptors in adipose tissue of cancer patients. (2016)
  • Author(s): Shimabukuro M , Sato H, Izaki H, Fukuda D, Uematsu E,Hirata Y, Yagi S, Soeki T, Sakaue H, Kanayama H, Masuzaki H, Sata M
  • Journal Title: Biofactors. Volume: 印刷中 Issue: 4 Pages: 397-406
  • DOI: 10.1002/biof.1287
  • Peer Reviewed
• [Journal Article] Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue (2016)
  • Author(s): Nishimoto S, Fukuda D, Higashikuni Y, Tanaka K, Hirata Y, Murata C, Kim-Kaneyama JR, Sato F, Bando M, Yagi S, Soeki T, Hayashi T, Imoto I, Sakaue H, Shimabukuro M, Sata M.
  • Journal Title: Sci Adv. Volume: 2(3) Issue: 3
  • DOI: 10.1126/sciadv.1501332
  • Peer Reviewed / Open Access
• [Journal Article] Effects of dietary phosphate on glucose and lipid metabolism. (2016)
  • Author(s): Abuduli M, Ohminami H, Otani T, Kubo H, Ueda H, Kawai Y, Masuda M, Yamanaka-Okumura H, Sakaue H, Yamamoto H, Takeda E, Taketani Y.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 301
  • Peer Reviewed
• [Journal Article] DNA Methylation Suppresses Leptin Gene in 3T3-L1 Adipocytes. (2016)
  • Author(s): Kuroda M, Tominaga A, Nakagawa K, Nishiguchi M, Sebe M, Miyatake Y, Kitamura T, Tsutsumi R, Harada N, Nakaya Y, Sakaue H.
  • Journal Title: PLoS ONE. Volume: 11 Issue: 8 Pages: e0160532-e0160532
  • DOI: 10.1371/journal.pone.0160532
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] PET/CTを用いた骨格筋糖取り込み能の測定 (2019)
  • Author(s): 三島 優奈, 堤 理恵, 宮武 由実子, 末政 直哉, 大谷 環樹, 兒玉 直子, 丹波 洋介, 黒田 雅士, 升本 早枝子, 阪上 浩
  • Organizer: 第３９回日本肥満学会
• [Presentation] 脂肪組織における炎症性サイトカインMCP-1の発現を制御する新たな転写因子の同定 (2018)
  • Author(s): 黒田 雅士, 石川 悦子, 宇川 菜穂, 川端 康代, 佐々木 和佳, 升本 早枝子, 堤 理恵, 阪上 浩
  • Organizer: 第91回日本内分泌学
• [Presentation] 2019120312 脱メチル化3T3-L1脂肪細胞のインスリン感受性調節因子の探索 (2018)
  • Author(s): 佐々木 和佳, 黒田 雅士, 石川 悦子, 宇川 菜穂, 川端 康代, 升本 早枝子, 堤 理恵, 阪上 浩
  • Organizer: 第３９回日本肥満学会
• [Presentation] 肥大化脂肪細胞における転写因子IRF7の同定と生理的役割の検討 (2018)
  • Author(s): 川端 康代, 黒田 雅士, 石川 悦子, 宇川 菜穂, 佐々木 和佳, 升本 早枝子, 堤 理恵, 阪上 浩
  • Organizer: 第３９回日本肥満学会
• [Presentation] 肥満脂肪組織病態学の最先端 肥満病態形成におけるIRF7の二つの役割 (2018)
  • Author(s): 黒田 雅士, 阪上 浩
  • Organizer: 第３９回日本肥満学会
  • Invited
• [Presentation] 栄養から考える肥満・サルコペニア 疾患性サルコペニアにおける栄養 骨格筋分解系に過剰栄養が与える影響 (2018)
  • Author(s): 堤 理恵, 阪上 浩
  • Organizer: 第３９回日本肥満学会
  • Invited
• [Presentation] 肥大化脂肪細胞における転写因子IRF7の同定と機能解析 (2018)
  • Author(s): 宇川 菜穂, 黒田 雅士, 石川 悦子, 升本 早枝子, 堤 理恵, 原田 永勝, 阪上 浩
  • Organizer: 第61回日本糖尿病学会
• [Presentation] 脂肪組織慢性炎症及びNASH病態形成に対するMFG-E8の関与 (2018)
  • Author(s): 黒田 雅士, 西口 実佐, 小野山 瑠美, 石川 悦子, 宇川 菜穂, 升本 早枝子, 堤 理恵, 原田 永勝, 阪上 浩
  • Organizer: 第61回日本糖尿病学会
• [Presentation] 謝破綻と疾患 重症患者におけるエネルギー代謝破綻 (2018)
  • Author(s): 堤 理恵, 阪上 浩
  • Organizer: 第72回日本栄養・食糧学会大会
  • Invited
• [Presentation] 肥満脂肪組織病態学-白色・褐色脂肪細胞制御 (2017)
  • Author(s): 阪上 浩
  • Organizer: 第38回日本肥満学会
  • Invited
• [Presentation] 肥大化脂肪細胞における転写因子IRF-7の同定と機能解析 (2017)
  • Author(s): 西口 実佐、阪上 浩
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 肥大化脂肪細胞における転写因子IRF7の同定と機能解析 (2017)
  • Author(s): 宇川 菜穂、阪上 浩
  • Organizer: 第38回日本肥満学会
• [Presentation] 肥大化脂肪細胞における転写因子IRF7の同定と機能解析 (2016)
  • Author(s): 西口 実佐、黒田 雅士、小野山 瑠美、宇川 菜穂、堤 理恵、原田 永勝、阪上 浩
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウンビル（東京都）
  • Year and Date: 2016-10-07
• [Book] 新時代の臨床糖尿病学【脂肪細胞の分化と機能】 (2016)
  • Author(s): 黒田 雅士, 阪上 浩
  • Total Pages: 5
  • Publisher: 日本臨床
• [Book] 実験医学【「解明」から「制御」へ、肥満症のメディカルサイエンス】 (2016)
  • Author(s): 黒田 雅士, 阪上 浩
  • Total Pages: 7
  • Publisher: 羊土社
• [Book] Clinical Calcium 【肥満・2型糖尿病におけるビタミンD・カルシウムの役割】 (2016)
  • Author(s): 黒田 雅士, 阪上 浩
  • Total Pages: 5
  • Publisher: メディカルトレビューン社
• [Remarks] 徳島大学大学院 医歯薬学研究部 代謝栄養学分野ホームページ
  • URL: https://taishaeiyo.jimdo.com