Endocrine functions of osteocalcin

• Project/Area Number: 26861553
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Functional basic dentistry
• Research Institution: Kyushu University
• Principal Investigator: Mizokami Akiko 九州大学, 歯学研究院, 講師 (70722487)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オステオカルシン / 性差 / アディポネクチン / テストステロン / 糖代謝 / インクレチン / エネルギー代謝 / 骨

Outline of Final Research Achievements

Osteocalcin, in its uncarboxylated form (GluOC), regulates energy metabolism by stimulating insulin secretion, pancreatic β-cell proliferation, and adiponectin expression in the adipocytes. In this study, we showed that there is a sex difference in the effect of GluOC on glucose homeostasis in mouse models. Long-term oral administration of GluOC improved glucose tolerance and decreased adipocyte size in female mice. However, the same treatment caused glucose intolerance, insulin resistance, and adipocyte hypertrophy in male mice. In addition, such administrations of GluOC increased circulating testosterone (T) and decreased serum adiponectin level. These phenotypes disappeared when mice were orchidectomized, and restored again by T supplementation. Moreover, female mice supplemented with T exhibited similar responses to GluOC as male mice. These results suggest that deleterious effect of GluOC is mediated in part by increased circulating T level.

Research Products

• [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
• [Journal Article] オステオカルシンとエネルギー代謝 (2017)
  • Author(s): 溝上顕子、川久保（安河内）友世、平田雅人
  • Journal Title: 骨粗鬆症治療 Volume: 16 Pages: 33-38
• [Journal Article] An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration (2016)
  • Author(s): Mizokami, A., Wang, DG, Tanaka, M., Gao, J., Takeuchi, H., Matsui, T. and Hirata, M.
  • Journal Title: Biosci. Biotechnol. Biochem. Volume: 80 Issue: 11 Pages: 2176-2183
  • DOI: 10.1080/09168451.2016.1214530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential roles of carboxylated and uncarboxylated osteocalcin in prostate cancer growth (2016)
  • Author(s): Hayashi, Y., Kawakubo-Yasukochi, T., Mizokami, A., Takeuchi, H., Nakamura, S. and Hirata, M.
  • Journal Title: J. Cancer Volume: 7 Issue: 12 Pages: 1605-1609
  • DOI: 10.7150/jca.15523
  • NAID: 120006900040
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential role of SNAP-25 phosphorylation by protein kinases A and C in the regulation of SNARE complex formation and exocytosis in PC12 cells (2016)
  • Author(s): Gao, J., Hirata, Makiko, Mizokami, A., Zhao, J., Takahashi, I., Takeuchi, H. and Hirata, Masato
  • Journal Title: Cell. Signal. Volume: 28 Issue: 5 Pages: 425-437
  • DOI: 10.1016/j.cellsig.2015.12.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Uncarboxylated osteocalcin increases serum nitric oxide levels and ameliorates hypercholesterolemia in mice fed an atherogenic diet. (2016)
  • Author(s): Kondo, A., Kawakubo-Yasukochi, T., Mizokami, A., Chishaki, S., Takeuchi, H. and Hirata, M.
  • Journal Title: Electronic J Biol Volume: 13 Pages: 22-28
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet (2016)
  • Author(s): Yasutake Y., Mizokami A., Kawakubo-Yasukochi T., Chishaki S., Takahashi I., Takeuchi H., Hirata M.
  • Journal Title: Am. J. Physiol. Endocrinol. Metab. Volume: 310 Issue: 8 Pages: E662-E675
  • DOI: 10.1152/ajpendo.00334.2015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Organ network for preventing metabolic syndromes with a reference to the roles of osteocalcin (2015)
  • Author(s): 溝上顕子、*川久保(安河内)友世、竹内弘、平田雅人
  • Journal Title: Folia Pharmacologica Japonica Volume: 145 Issue: 4 Pages: 201-205
  • DOI: 10.1254/fpj.145.201
  • NAID: 130005061556
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin. (2015)
  • Author(s): Tsuka, S., Aonuma, F., Higashi, S., Ohsumi, T., Nagano, K., Mizokami, A., Kawakubo-Yasukochi, T., Masaki, C., Hosokawa, R. and Hirata, M. and Takeuchi, H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 459 Issue: 3 Pages: 437-442
  • DOI: 10.1016/j.bbrc.2015.02.123
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Signaling pathway for adiponectin expression in adipocytes by osteocalcin. (2015)
  • Author(s): Otani, T., Mizokami, A., Hayashi, Y., Gao, J., Mori, Y., Nakamura, S., Takeuchi, H. and Hirata, M.
  • Journal Title: Cellular Signalling Volume: 27 Issue: 3 Pages: 532-544
  • DOI: 10.1016/j.cellsig.2014.12.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. (2014)
  • Author(s): Mizokami, A., Yasutake, Y., Higashi, S., Kawakubo-Yasukochi, T., Chishaki, S., Takahashi, I., Takeuchi, H. and Hirata, M.
  • Journal Title: Bone Volume: 69 Pages: 68-79
  • DOI: 10.1016/j.bone.2014.09.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C-Related Catalytically Inactive Protein (PRIP) regulates lipolysis in adipose tissue by modulating the phosphorylation of hormone-sensitive lipase (2014)
  • Author(s): T. Okumura, K. Harada, K. Oue, J. Zhang, S. Asano, M. Hayashiuchi, A. Mizokami, H. Tanaka, M. Irifune, N. Kamata, M. Hirata, and T. Kanematsu.
  • Journal Title: PLoS One Volume: 9 Issue: 6 Pages: e100559-e100559
  • DOI: 10.1371/journal.pone.0100559
  • Peer Reviewed / Open Access
• [Presentation] An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. (2016)
  • Author(s): Mizokami, A. and Hirata, M.
  • Organizer: The Food Factor I Barcelona Conference
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-11-01
  • Int'l Joint Research
• [Presentation] Oral Administration of Osteocalcin Improves Glucose Utilization by Stimulating Glucagon-Like Peptide-1 Secretion. (2016)
  • Author(s): Hirata, M., Mizokami, A. and Kawakubo-Yasukochi, T.
  • Organizer: International Conference on Obesity and Metabolic Syndrome
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-09-01
  • Int'l Joint Research / Invited
• [Presentation] オステオカルシンの代謝改善効果におけるGLP-1の役割 (2016)
  • Author(s): 溝上顕子、安河内（川久保）友世、竹内弘、平田雅人
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 札幌市
  • Year and Date: 2016-08-24
• [Presentation] Sex difference in the effects of uncarboxylated osteocalcin on glucose homeostasis. (2016)
  • Author(s): Sakura Chishaki, Akiko Mizokami, Masato Hirata
  • Organizer: The 9th Korea-Japan Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] Sex difference in osteocalcin action (2016)
  • Author(s): 溝上 顕子
  • Organizer: Gendered Innovationsが拓く明るい未来. Symposium for Diversity Initiatives and Gendered Innovations 多様性の推進と性差に着目した技術革新
  • Place of Presentation: 福岡市
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] The effect of uncarboxylated osteocalcin on glucose utilization in mice. (2016)
  • Author(s): Mizokami A., Yasutake Y., Chishaki S., Kawakubo-Yasukochi T., Takeuchi H., Hirata M.
  • Organizer: The 13th Asia Pacific Federation of Pharmacologists (APFP) Meeting.
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2016-02-01
  • Int'l Joint Research
• [Presentation] Gender difference in the endocrine function of osteocalcin. (2015)
  • Author(s): Mizokami A., Yasutake Y., Hirata M.
  • Organizer: The 63rd Annual Meeting of Japanese Association for Dental Research
  • Place of Presentation: 福岡市
  • Year and Date: 2015-10-30
  • Int'l Joint Research
• [Presentation] 長期的なオステオカルシンの経口投与による代謝の改善とその性差 (2015)
  • Author(s): 溝上 顕子、安武 雄、安河内 友世、平田 雅人
  • Organizer: 第５７回歯科基礎医学会学術大会・総会
  • Place of Presentation: 新潟市
  • Year and Date: 2015-09-11
• [Presentation] 継続的なオステオカルシンの経口投与による糖代謝への影響とその体内動態 (2015)
  • Author(s): 溝上 顕子、安武 雄、東 泉、川久保―安河内 友世、竹内 弘、平田 雅人
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-03-18 – 2015-03-21
• [Presentation] 長期的なオステオカルシンの経口投与がマウスの代謝に及ぼす影響とその性差 (2014)
  • Author(s): 安武 雄、溝上 顕子、川久保－安河内 友世、平田 雅人
  • Organizer: 第８７回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] オステオカルシン経口投与時の体内動態と糖代謝への作用 (2014)
  • Author(s): 溝上 顕子、安武 雄、東泉、川久保－安河内 友世、高橋 一郎、竹内 弘、平田 雅人
  • Organizer: 第５６回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] 九州大学大学院歯学研究院口腔細胞工学ホームページ
  • URL: http://www.mcb.dent.kyushu-u.ac.jp/index.html
• [Remarks] 九州大学 2014年10月6日プレスリリース
  • URL: http://www.kyushu-u.ac.jp/pressrelease/2014_10_06.pdf
• [Patent(Industrial Property Rights)] メタボリックシンドロームの予防または改善のための食用組成物 (2016)
  • Inventor(s): 平田 雅人、溝上 顕子、安河内 友世、山下 泰寿
  • Industrial Property Rights Holder: 国立大学法人九州大学、株式会社 クリーン・エコバランス
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-08-18
  • Overseas
• [Patent(Industrial Property Rights)] 非または低カルボキシル化オステオカルシンの製造方法およびその利用 (2015)
  • Inventor(s): 平田 雅人、溝上 顕子、安河内 友世
  • Industrial Property Rights Holder: 国立大学法人九州大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-161238
  • Filing Date: 2015-08-18
• [Patent(Industrial Property Rights)] メタボリックシンドロームの予防または改善のための食用組成物 (2015)
  • Inventor(s): 平田 雅人、溝上 顕子、山下 泰寿安河内 友世、
  • Industrial Property Rights Holder: 国立大学法人九州大学、株式会社 クリーン・エコバランス
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-161239
  • Filing Date: 2015-08-18