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Roles of osteocalcin for energy metabolism

Research Project

Project/Area Number 17H01595
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionFukuoka Dental College

Principal Investigator

Hirata Masato  福岡歯科大学, 口腔歯学部, 客員教授 (60136471)

Co-Investigator(Kenkyū-buntansha) 竹内 弘  九州歯科大学, 歯学部, 教授 (70304813)
溝上 顕子  九州大学, 歯学研究院, 准教授 (70722487)
御船 弘治  久留米大学, 医学部, 客員准教授 (70174117)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2019: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Fiscal Year 2018: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2017: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
Keywordsオステオカルシン / インスリン / インクレチン / メタボリックシンドローム / 糖・脂質代謝 / 脂肪細胞 / エピゲノム / 糖代謝
Outline of Final Research Achievements

Osteocalcin is a bone-derived hormone that in its uncarboxylated form (GluOC) plays an important role in glucose and energy metabolism by stimulating insulin secretion and pancreatic beta-cell proliferation. In the study (1) We clarified the molecular mechanism by which GluOC triggered cell death of adipocytes, thus resulting in the decrease of abdominal adipose tissues and the increase of adiponectin secretion. (2) We showed that the beneficial effect of GluOC on metabolic status such as insulin secretion, glucose tolerance and others is mediated predominantly by glucagon-like peptide-1 (GLP-1) signaling, rather than direct effect by GluOC itself. (3) We observed that maternal diet during pregnancy influenced the health of offspring in adulthood, and administration of GluOC during gestation improves metabolic status in female offspring mice in adulthood, indicating that eneficial effects of GluOC administration on metabolic status are transmitted to the offspring beyond generation.

Academic Significance and Societal Importance of the Research Achievements

本研究では、オステオカルシンの内分泌作用のメカニズムの一端を解明した。特に脂肪細胞への直接的な作用において、高濃度のオステオカルシンが巨大脂肪細胞の細胞死(ネクロトーシス)を誘導するシグナリング経路を解明した学術的意義は大きい。また、オステオカルシン投与が全身的なメタボ状態(空腹時血糖、耐糖能、インスリン抵抗性など)を改善するのは、直接的効果ではなく、消化管ホルモンであるGLP-1を介する効果が大きいという発見の意義も大きい。加えて、疾病胎児起源説におけるオステオカルシンの有益性に関する発見も興味深い。今回の成果は、生活習慣病に対する新たな生理・薬理学的アプローチにつながる可能性がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (43 results)

All 2020 2019 2018 2017

All Journal Article (14 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 13 results,  Open Access: 12 results,  Acknowledgement Compliant: 1 results) Presentation (28 results) (of which Int'l Joint Research: 5 results,  Invited: 7 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol.2020

    • Author(s)
      Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
    • Journal Title

      Journal of Endocrinology

      Volume: 244 Issue: 2 Pages: 285-296

    • DOI

      10.1530/joe-19-0288

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice2019

    • Author(s)
      Yamawaki Yosuke、Shirawachi Satomi、Mizokami Akiko、Nozaki Kanako、Ito Hikaru、Asano Satoshi、Oue Kana、Aizawa Hidenori、Yamawaki Shigeto、Hirata Masato、Kanematsu Takashi
    • Journal Title

      Neurochemistry International

      Volume: 131 Pages: 104563-104563

    • DOI

      10.1016/j.neuint.2019.104563

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow2019

    • Author(s)
      Asano, S., Ikura, Y., Nishimoto, M., Yamawaki, Y., Hamao, K., Kamijo, K., Hirata, M. and Kanematsu, T.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 12729-12729

    • DOI

      10.1038/s41598-019-49156-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice2019

    • Author(s)
      Furukawa Tomonori、Nikaido Yoshikazu、Shimoyama Shuji、Ogata Yoshiki、Kushikata Tetsuya、Hirota Kazuyoshi、Kanematsu Takashi、Hirata Masato、Ueno Shinya
    • Journal Title

      Journal of Anesthesia

      Volume: 33 Issue: 4 Pages: 531-542

    • DOI

      10.1007/s00540-019-02663-z

    • NAID

      40021971791

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure2019

    • Author(s)
      Kanematsu T, Oue K, Okumura T, Harada K, Yamawaki Y, Asano S, Mizokami A, Irifune M, Hirata M
    • Journal Title

      J Oral Biosci

      Volume: 61(2) Issue: 2 Pages: 65-72

    • DOI

      10.1016/j.job.2019.04.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes regulated by the activation of p300.2018

    • Author(s)
      Otani, T., Matsuda, M., Mizokami, A., Kitagawa, N., Takeuchi, H., Jimi, E.,Inai, T., and Hirata, M.
    • Journal Title

      Cell Death Disease

      Volume: 9 Issue: 12 Pages: 1194-1210

    • DOI

      10.1038/s41419-018-1257-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Poor motor-function recovery after spinal-cord injury in anxiety-model mice with phospholipase related catalytically inactive protein type 1 knockout.2018

    • Author(s)
      Taka Fujita, Gentaro Kumagai, Xizhe Liu, Kanichiro Wada, Toshihiro Tanaka, Hitoshi Kudo, Toru Asari, Tatsuhiro Fukutoku, Ayako Sasaki, Yohshiro Nitobe, Yoshikazu Nikaido, Ken-Ichi Furukawa, Masato Hirata, Takashi Kanematsu, Shinya Ueno, Yasuyuki Ishibash
    • Journal Title

      Journal of Neurotrauma

      Volume: 印刷中 Issue: 12 Pages: 1379-1386

    • DOI

      10.1089/neu.2017.5492

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 骨による全身の糖・エネルギー代謝調節機構2018

    • Author(s)
      溝上 顕子、平田 雅人
    • Journal Title

      FOOD Style 21

      Volume: 22 Pages: 50-53

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Phospholipase C-related, but catalytically inactive protein (PRIP) up-regulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling.2017

    • Author(s)
      Murakami, A., Matsuda, M., Harada, Y., Hirata, M.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 292 Issue: 19 Pages: 7994-8006

    • DOI

      10.1074/jbc.m117.784777

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phospholipase C-related but catalytically inactive proteins regulate ovarian follicle development.2017

    • Author(s)
      Matsuda, M., Hirata, M.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 292 Issue: 20 Pages: 8369-8380

    • DOI

      10.1074/jbc.m116.759928

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Propofol anesthesia is reduced in Phospholipase C-related inactive protein type-1 knockout mice2017

    • Author(s)
      Nikaido Y, Furukawa T, Shimoyama S, Yamada J, Migita K, Koga K, Kushikata T, Hirota K, Kanematsu T, Hirata M, Ueno S
    • Journal Title

      The Journal of pharmacology and experimental therapeutics

      Volume: 361(3) Issue: 3 Pages: 367-374

    • DOI

      10.1124/jpet.116.239145

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Uncarboxylated osteocalcin induces antitumor immunity against mouse melanoma cell growth.2017

    • Author(s)
      Hayashi Y, Kawakubo-Yasukochi T, Mizokami A, Hazekawa M, Yakura T, Naito M, Takeuchi H, Nakamura S, Hirata M.
    • Journal Title

      J Cancer

      Volume: 8 Issue: 13 Pages: 2478-2486

    • DOI

      10.7150/jca.18648

    • NAID

      120006900041

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling2017

    • Author(s)
      Asano Satoshi、Taniguchi Yuri、Yamawaki Yosuke、Gao Jing、Harada Kae、Takeuchi Hiroshi、Hirata Masato、Kanematsu Takashi
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 5408-5408

    • DOI

      10.1038/s41598-017-05908-7

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Osteocalcin and its endocrine functions.2017

    • Author(s)
      Mizokami A., Kawakubo-Yasukochi T., Hirata M.
    • Journal Title

      Biochem Pharmacol.

      Volume: 132 Pages: 1-8

    • DOI

      10.1016/j.bcp.2017.02.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] オステオカルシンが制御する胎内栄養環境応答と疾病素因形成2020

    • Author(s)
      安河内(川久保)友世、溝上顕子、平田雅人
    • Organizer
      第93回日本薬理学会年
    • Related Report
      2019 Annual Research Report
  • [Presentation] 骨基質タンパク質オステオカルシンが PC12 の細胞増殖と神経様細胞分化に及ぼす影響2020

    • Author(s)
      安藤瑛香、東泉、溝上顕子、大住伴子、渡邉誠之、平田雅人、竹内弘
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] シグナル分子PRIPは卵胞成熟制御に関与する2019

    • Author(s)
      松田美穂、自見英治郎、平田雅人
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脂肪細胞におけるGPRC6Aシグナリングの生理的意義2019

    • Author(s)
      向井 悟、溝上顕子、大谷崇仁、松田美穂、竹内 弘、自見英治郎、平田雅人
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] オステオカルシンの代謝改善効果におけるGLP-1受容体シグナルの役割2019

    • Author(s)
      溝上顕子、向井 悟、竹内 弘、自見英治郎、平田雅人
    • Organizer
      第61回歯科基礎医学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Serendipity を求めて2019

    • Author(s)
      平田雅人
    • Organizer
      第61回歯科基礎医学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 脂肪細胞を細胞死へと導く骨基質タンパク質 Osteocalcin2019

    • Author(s)
      大谷崇仁、松田美穂、溝上顕子、北河憲雄、自見英治郎、稲井哲一朗、平田雅人
    • Organizer
      第61回歯科基礎医学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The effect of maternal uncarboxylated osteocalcin on the metabolic properties of next generation2019

    • Author(s)
      Kawakubo-Yasukochi, T., Kondo, A., Mizokami, A. and Hirata, M.
    • Organizer
      DOHaD World Congress 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Oral administration of osteocalcin, bone-derived hormone, improves the performance of voluntary exercise concomitant with the amelioration of fat utilization in mice2019

    • Author(s)
      Tajiri, Y., Sakai, Y., Mifune, H and Hirata, M.
    • Organizer
      The 55th Annual Meeting of the European Association for the Study of Diabetes (EASD)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Adipocyte-specific GPRC6A ablation induces diet-induced obesity by inhibiting lipolysis2019

    • Author(s)
      Mizokami, A., Mukai, S., Otani, T., Takeuchi, H., Jimi, E. and Hirata, M.
    • Organizer
      2019 International Conference on Obesity and Metabolic Syndrome
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Glucagon-like peptide-1 receptor signaling is required for an osteocalcin-mediated improvement of glucose tolerance2019

    • Author(s)
      Mizokami, A. and Hirata, M.
    • Organizer
      American Diabetes Association (ADA) 79th Scientific Sessions
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 骨は内分泌器官2019

    • Author(s)
      平田雅人
    • Organizer
      第73回日本口腔科学会大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 脂肪細胞表面受容体GPRC6Aを介した脂肪蓄積機構2018

    • Author(s)
      溝上 顕子、松田 美穂、竹内 弘、安河内友世、自見英治郎、平田 雅人
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Programmed necrosis of adipocytes induced by high-dose osteocalcin2018

    • Author(s)
      Otani T, Hirata M, Mizokami A, Kitagawa N, Jimi E. and Inai T.
    • Organizer
      The 18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
  • [Presentation] PRIPによる脂肪細胞のインスリンシグナリングの調節2018

    • Author(s)
      高 靖、溝上 顕子、竹内 弘、自見 英治郎、平田 雅人
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Uncarboxylated osteocalcin has a protective effect against UVB-induced production of reactive oxygen species in human keratinocytes2018

    • Author(s)
      向井 悟、溝上 顕子、高 靖、自見英治郎、平田 雅人
    • Organizer
      第60回歯科基礎医学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Protective effect by uncarboxylated osteocalcin against UVB-induced reactive oxygen species in HaCaT keratinocytes2018

    • Author(s)
      溝上 顕子、久保山奈緒、向井 悟、高 靖、自見英治郎、平田 雅人
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] A novel molecule involved in the regulation of insulin signaling mediated by internalization of insulin receptor in adipocyte2018

    • Author(s)
      高 靖、溝上 顕子、竹内 弘、自見 英治郎、平田 雅人
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Induction of necroptosis in adipocytes by osteocalcin2018

    • Author(s)
      大谷 崇仁、溝上 顕子、北河 憲雄、松田 美穂、自見英治郎、稲井哲一朗、平田 雅人
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 妊娠母体が摂取したオステオカルシンが次世代に及ぼす影響2017

    • Author(s)
      川久保-安河内友世、近藤皓彦、溝上顕子、平田雅人
    • Organizer
      第6回日本DOHaD学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Sex differences in the regulation of energy metabolism by osteocalcin2017

    • Author(s)
      Mizokami, A., Kawakubo-Yasukochi, T. and Hirata, M.
    • Organizer
      2017 International Conference on Obesity and Metabolic Syndrome
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 脂肪細胞特異的GPRC6A欠損が全身代謝に与える影響2017

    • Author(s)
      溝上顕子、竹内 弘、自見英治郎、平田雅人
    • Organizer
      第59回歯科基礎医学会学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] シグナル調節分子PRIPの破骨細胞分化における役割2017

    • Author(s)
      松田美穂、自見英治郎、平田雅人
    • Organizer
      第59回歯科基礎医学会学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 動脈硬化の病態におけるオステオカルシンの役割2017

    • Author(s)
      近藤皓彦、川久保-安河内友世、溝上顕子、自見英治郎、平田雅人
    • Organizer
      第59回歯科基礎医学会学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] オステオカルシンによる脂肪細胞へのネクロトーシス誘導メカニズムの解明2017

    • Author(s)
      大谷崇仁、溝上顕子、北河憲雄、稲井哲一朗、平田雅人
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 脂肪組織特異的GPRC6A欠損マウスの作製とその脂質代謝異常の解析2017

    • Author(s)
      向井悟、溝上顕子、樗木さくら、松田美穂、竹内弘、大谷崇仁、自見英治郎、平田雅人
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] インスリン受容体基質のリン酸化制御におけるPRIPの役割2017

    • Author(s)
      高靖、溝上顕子、竹内弘、自見英治郎、平田雅人
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] シグナル分子PRIPのカルシウムを介した破骨細胞分化制御への関わり2017

    • Author(s)
      松田美穂、村上絢子、自見英治郎、平田雅人
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] 自発運動増強用組成物2019

    • Inventor(s)
      学校法人久留米大学、平田雅人
    • Industrial Property Rights Holder
      学校法人久留米大学、平田雅人
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-167223
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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