Roles of osteocalcin for energy metabolism

• Project/Area Number: 17H01595
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Fukuoka 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: ¥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。

Research Products

• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice (2019)
  • 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
  • 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 furrow (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure (2019)
  • 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
  • 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
  • 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
  • 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
• [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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Propofol anesthesia is reduced in Phospholipase C-related inactive protein type-1 knockout mice (2017)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling (2017)
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
  • Invited
• [Presentation] 脂肪細胞を細胞死へと導く骨基質タンパク質 Osteocalcin (2019)
  • 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
  • Invited
• [Presentation] The effect of maternal uncarboxylated osteocalcin on the metabolic properties of next generation (2019)
  • Author(s): Kawakubo-Yasukochi, T., Kondo, A., Mizokami, A. and Hirata, M.
  • Organizer: DOHaD World Congress 2019
  • 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 mice (2019)
  • 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)
  • Int'l Joint Research / Invited
• [Presentation] Adipocyte-specific GPRC6A ablation induces diet-induced obesity by inhibiting lipolysis (2019)
  • Author(s): Mizokami, A., Mukai, S., Otani, T., Takeuchi, H., Jimi, E. and Hirata, M.
  • Organizer: 2019 International Conference on Obesity and Metabolic Syndrome
  • Int'l Joint Research / Invited
• [Presentation] Glucagon-like peptide-1 receptor signaling is required for an osteocalcin-mediated improvement of glucose tolerance (2019)
  • Author(s): Mizokami, A. and Hirata, M.
  • Organizer: American Diabetes Association (ADA) 79th Scientific Sessions
  • 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
  • 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
  • Invited
• [Presentation] Programmed necrosis of adipocytes induced by high-dose osteocalcin (2018)
  • 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
• [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
• [Presentation] Uncarboxylated osteocalcin has a protective effect against UVB-induced production of reactive oxygen species in human keratinocytes (2018)
  • 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
• [Presentation] Protective effect by uncarboxylated osteocalcin against UVB-induced reactive oxygen species in HaCaT keratinocytes (2018)
  • 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
• [Presentation] A novel molecule involved in the regulation of insulin signaling mediated by internalization of insulin receptor in adipocyte (2018)
  • 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
• [Presentation] Induction of necroptosis in adipocytes by osteocalcin (2018)
  • 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
• [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
• [Presentation] Sex differences in the regulation of energy metabolism by osteocalcin (2017)
  • Author(s): Mizokami, A., Kawakubo-Yasukochi, T. and Hirata, M.
  • Organizer: 2017 International Conference on Obesity and Metabolic Syndrome
  • 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
• [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
• [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
• [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
• [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
• [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
• [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
• [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