Development of in vitro and in vivo assay systems to elucidate molecular mechanism suppressing obesity

• Project/Area Number: 26670032
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: SUGATANI JUNKO 静岡県立大学, 薬学部, 教授 (30098131)
• Co-Investigator(Kenkyū-buntansha): YAMAGUCHI MASAHIKO 静岡県立大学, 薬学部, 助教 (00632639)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: PAF / PAF受容体 / PAF受容体欠損マウス / PAF受容体フロックスマウス / 肥満 / 褐色脂肪細胞 / UCP1 / UCP1クレマウス / ＵＣＰ１ / PAF受容体ノックアウトマウス / β3アドレナリン受容体 / コンディショナルノックアウトマウス

Outline of Final Research Achievements

We investigated how PAF/PAF receptor signaling suppresses energy expenditure in vitro and in vivo. 　In cell lines differentiated to brown adipocytes, the effect of PAF to expression of UCP1 was rather low. In PAF receptor-knockout (PAFR-KO) mice, body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-alpha mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. We also generated PAFR-floxed mice and crossed them with Adiponectin-Cre or Ucp1-Cre mice to generate white or brown adipocyte specific PAFR-KO mice, respectively. These knockout mice could be useful for studying PAF/PAF receptor dependent energy expenditure in vivo.

Research Products

• [Journal Article] Threonine-408 Regulates the Stability of the Human Pregnane X Receptor Through its Phosphorylation and the CHIP/Chaperone- Autophagy Pathway. (2016)
  • Author(s): Sugatani J, Noguchi Y, Hattori Y, Yamaguchi M, Yamazaki Y, Ikari A
  • Journal Title: Drug Metab Dispos Volume: 44 Issue: 1 Pages: 137-150
  • DOI: 10.1124/dmd.115.066308
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation. (2015)
  • Author(s): Yamaguchi, M., Matsui, M., Higa, R., Yamazaki, Y., Ikari, A., Miyake, M., Miwa, M., Ishii, S., Sugatani, J., and Shimizu, T.
  • Journal Title: Biochem. Pharmacol. Volume: 93 Issue: 4 Pages: 482-495
  • DOI: 10.1016/j.bcp.2014.12.022
  • Peer Reviewed / Open Access
• [Journal Article] Hyperosmolarity-Induced Down-Regulation of Claudin-2 Mediated by Decrease in PKCβ-Dependent GATA-2 in MDCK Cells. (2015)
  • Author(s): Ikari A, Fujii N, Hahakabe S, Hayashi H, Yamaguchi M, Yamazaki Y, Endo S, Matsunaga T, Sugatani J
  • Journal Title: J Cell Physiol Volume: 230 Issue: 11 Pages: 2776-2787
  • DOI: 10.1002/jcp.25004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of a Cyclic Adenosine Monophosphate-Dependent Signal in the Diet-Induced Canalicular Trafficking of Adenosine Triphosphate-Binding Cassette Transporter g5/g8. (2015)
  • Author(s): Yamazaki, Y., Yasui, K., Hashizume, T., Suto, A., Mori, A., Murata, Y., Yamaguchi, Y., Ikari, A., Sugatani, J.
  • Journal Title: Hepatology Volume: 62 Issue: 4 Pages: 1215-1226
  • DOI: 10.1002/hep.27914
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antiobese function of platelet-activating factor : increased adiposity in platelet-activating factor receptor-deficient mice with age (2014)
  • Author(s): Sugatani, J., Sadamitsu, S., Yamaguchi, M., Yamazaki, Y., Higa, R., Hattori, Y., Uchida, T., Ikari, A., Sugiyama, W., Watanabe, T., Ishii, S., Miwa, M., and Shimizu, T
  • Journal Title: FASEB J Volume: 28 Issue: 1 Pages: 440-452
  • DOI: 10.1096/fj.13-233262
  • Peer Reviewed / Open Access
• [Journal Article] Tight junctional localization of claudin-16 is regulated by syntaxin 8 in renal tubular epithelial cells (2014)
  • Author(s): Akira Ikari, Chie Tonegawa, Ayumi Sanada, Toru Kimura, Hideki Sakai, Hisayoshi Hayashi, Hajime Hasegawa, Masahiko Yamaguchi, Yasuhiro Yamazaki, Satoshi Endo, Toshiyuki Matsunaga, Junko Sugatani
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 19 Pages: 13112-13123
  • DOI: 10.1074/jbc.m113.541193
  • Peer Reviewed / Open Access
• [Journal Article] Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells. (2014)
  • Author(s): kari A, Watanabe R, Sato T, Taga S, Shimobaba S, Yamaguchi M, Yamazaki Y, Endo S, Matsunaga T, Sugatani J
  • Journal Title: Biochim. Biophys. Acta. Volume: 1843 Issue: 9 Pages: 2079-2088
  • DOI: 10.1016/j.bbamcr.2014.05.017
  • Peer Reviewed / Open Access
• [Journal Article] Threonine-290 regulates nuclear translocation of the human pregnane X receptor through its phosphorylation/dephosphorylation by Ca2+/calmodulin-dependent protein kinase II and protein phosphatase 1. (2014)
  • Author(s): Sugatani J, Hattori Y, Noguchi Y, Yamaguchi M, Yamazaki Y, Ikari A
  • Journal Title: Drug Metab. Dispos. Volume: 42 Issue: 10 Pages: 1708-1718
  • DOI: 10.1124/dmd.114.059139
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 血小板活性化因子受容体欠損で誘発された肥満マウスの慢性炎症反応とその制御機構の解析 (2015)
  • Author(s): 松井雅和、山口賢彦、須山大輔、宮武将之、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-02
• [Presentation] Threonine-408 regulates the stability of the human pregnane X receptor through its phosphorylation and the CHIP/chaperone- autophagy pathway. (2015)
  • Author(s): Junko Sugatani, Yuji Noguchi, Yoshiki Hattori, Masahiko Yamaguchi, Yasuhiro Yamazaki, Akira Ikari
  • Organizer: 20th North American ISSX Meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] 肥満誘発マウスの慢性炎症における血小板活性化因子の機能解明 (2015)
  • Author(s): 松井雅和、山口賢彦、須山大輔、宮武将之、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第79回日本生化学会中部支部例会・シンポジウム
  • Place of Presentation: 松本
  • Year and Date: 2015-05-23
• [Presentation] A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity and PAF/PAF receptor signaling up-regulates an energy expenditure inducer in adipocytes. (2015)
  • Author(s): Yamaguchi M, Matsui M, Yamazaki Y, Ikari A, Miwa M, Ishii S, Shimizu T, Sugatani J
  • Organizer: 6th International Conference on PLA2 and lipid mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-10
• [Presentation] Threonine-290 regulates nuclear translocation of the human pregnane X receptor through its phosphorylation/dephosphorylation by Ca2+/calmodulin-dependent protein kinase II and protein phosphatase 1. (2014)
  • Author(s): Yoshiki Hattori, Yuji Nogchi, Masahiko Yamaguchi, Yasuhiro Yamazaki, Akira Ikari, and Junko Sugatani
  • Organizer: The 2nd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2014-11-06
• [Presentation] Platelet-Activating Factor Receptor Deficiency Exacerbates Diet-induced Obesity and Glucose Metabolism Disorders. (2014)
  • Author(s): Yamaguchi Ｍ, Matsui Ｍ, Yamazaki Ｙ, Ikari A, Sugatani J
  • Organizer: The 2nd International Conference on Pharma and Food
  • Place of Presentation: 静岡
  • Year and Date: 2014-11-06
• [Presentation] 核内受容体PXRのスレオニン290のリン酸化/脱リン酸化反応が核内移行制御の中心的役割を担う (2014)
  • Author(s): 服部芳樹、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-17
• [Presentation] UGT1A1遺伝子発現制御異常に起因するグルクロン酸抱合体排泄機能障害に基づく疾患について (2014)
  • Author(s): 菅谷純子
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-17
  • Invited
• [Presentation] 核内受容体PXRの核内移行制御の中心的役割をスレオニン290リン酸化/脱リン酸化反応が担う (2014)
  • Author(s): 服部芳規、山口賢彦、山崎泰広、五十里彰、菅谷純子
  • Organizer: 第６０回日本薬学会東海支部大会
  • Place of Presentation: 三重
  • Year and Date: 2014-07-05
• [Presentation] 脂肪組織の慢性炎症化過程に関わる血小板活性化因子の機能解析 (2014)
  • Author(s): 山口賢彦、比嘉涼子、山崎泰広、五十里彰、石井聡、三輪匡男、清水孝雄、菅谷純子
  • Organizer: 第56回日本脂質生化学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-07
• [Presentation] Signal-mediated regulation of nuclear receptor PXR function. (2014)
  • Author(s): Junko Sugatani, Yoshiki Hattori, Yuji Noguchi, Masahiko Yamaguchi, Yasuhiro Yamazaki, Akira Ikari
  • Organizer: 20th International Symposium on Microsomes and Drug Oxidations
  • Place of Presentation: Stuttgart, Germany
  • Year and Date: 2014-05-18 – 2014-05-22
• [Remarks] 静岡県立大学薬学部生体情報分子解析学分野ホームページ
  • URL: http://w3pharm.u-shizuoka-ken.ac.jp/~rinsho/