Investigation of the role of pancreatic alpha cells in relationship between bone and systemic metabolism.

• Project/Area Number: 17K11649
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: Takeuchi Hiroshi 九州歯科大学, 歯学部, 教授 (70304813)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: メタボリックシンドローム / 骨代謝 / 糖代謝 / オステオカルシン / インクレチン / GLP-1 / 膵α細胞 / グルカゴン / エネルギー代謝 / 糖尿病 / 細胞・組織 / 生体分子 / シグナル伝達 / 歯学

Outline of Final Research Achievements

Continuous administration of the bone-derived osteocalcin (OC) resulted in increased GLP-1-producing cells in the pancreatic island in mice. Using acutely isolated mouse pancreatic islets and cultured α cells, we identified that OC directly acted on the receptor GPRC6A in pancreatic α cells to activate the cAMP pathway leading to the expression of the transcription factor Pax6. Then it was followed by promoting the expression of PC1/3 which converts proglucagon to GLP-1 instead of glucagon, and suppressing the expression of Pcsk1n that is an inhibitor of PC1/3 enzymatic activity. Thus, OC directly acts on the pancreatic α cells and induces switching its producing hormones.

Academic Significance and Societal Importance of the Research Achievements

本研究では、骨基質タンパク質オステオカルシンによる全身の糖・エネルギー代謝改善効果の新たな作用機序を解明した。オステオカルシンに、血糖値を上昇させるグルカゴンから血糖値を下げる働きを補助する GLP-1 へと膵α細胞が産生するホルモンをスイッチさせる働きがあることを見出して、その作用機構の一端を明らかにした本研究の成果は学術的に意義深い。また、生活習慣病に対する新たな予防・治療戦略の開発に寄与する可能性がある。

Research Products

• [Journal Article] Osteocalcin promotes proliferation, differentiation, and survival of PC12?cells (2021)
  • Author(s): Ando Eika、Higashi Sen、Mizokami Akiko、Watanabe Seiji、Hirata Masato、Takeuchi Hiroshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 557 Pages: 174-179
  • DOI: 10.1016/j.bbrc.2021.03.146
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of aging on bone metabolism: the involvement of complement C1q (2021)
  • Author(s): Aonuma Fumiko、Higashi Sen、Tsuka Shintaro、Ohsumi Tomoko、Masaki Chihiro、Hosokawa Ryuji、Takeuchi Hiroshi
  • Journal Title: Journal of Prosthodontic Research Volume: 65 Issue: 3 Pages: 393-399
  • DOI: 10.2186/jpr.JPOR_2019_644
  • NAID: 130008076958
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed / Open Access
• [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] Modification of TRPV4 activity by acetaminophen. (2020)
  • Author(s): Nakagawa, F., Higashi, S., Ando, E., Ohsumi, T., Watanabe, S., Takeuchi, H.
  • Journal Title: Heliyon Volume: 6 Issue: 1 Pages: e03301-e03301
  • DOI: 10.1016/j.heliyon.2020.e03301
  • 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] A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-indeuce osteogenesis. (2018)
  • Author(s): Urata M, Kokabu S, Matsubara T, Sugiyama G, Nakatomi C, Takeuchi H, Hirata TS, Aoki K, Tamura Y, Moriyama Y, Ayukawa Y, Matsuda M, Zhang M, Koyano K, Kitamura C, Jimi E.
  • Journal Title: J Cell Physiol. Volume: 1 Issue: 9 Pages: 1-11
  • DOI: 10.1002/jcp.26571
  • Peer Reviewed / Open Access
• [Journal Article] Celecoxib inhibits osteoblast differentiation independent of cyclooxygenase activity. (2018)
  • Author(s): Matsuyama, A., Higashi, S., Tanizaki, S., Morotomi, T., Washio, A., Ohsumi, T., Kitamura, C. and Takeuchi, H.
  • Journal Title: Clinical and Experimental Pharmacology and Physiology Volume: 45 Issue: 1 Pages: 75-83
  • DOI: 10.1111/1440-1681.12846
  • Peer Reviewed
• [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] Effect of acetaminophen on osteoblastic differentiation and migration of MC3T3-E1 cells. (2017)
  • Author(s): Nakatsu, Y., Nakagawa, F., Higashi, S., Ohsumi, T., Shiiba, S., Watanabe, S., Takeuchi, H.
  • Journal Title: Pharmacological reports Volume: 70 Issue: 1 Pages: 29-36
  • DOI: 10.1016/j.pharep.2017.07.006
  • Peer Reviewed
• [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
• [Presentation] 骨基質タンパク質オステオカルシンが PC12 細胞に及ぼす影響 (2020)
  • Author(s): 安藤瑛香，東泉，溝上顕子，渡邉誠之，平田雅人，竹内弘
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] PC12の細胞増殖と神経様分化に対する骨基質タンパク質オステオカルシンの影響 (2020)
  • Author(s): 安藤瑛香，東泉，溝上顕子，渡邉誠之，平田雅人，竹内弘
  • Organizer: 第73回日本薬理学会西南部会
• [Presentation] 細胞外グルコース濃度による上皮成長因子受容体動態の修飾 (2020)
  • Author(s): 山形真有香、冨永和弘、竹内弘
  • Organizer: 第53回日本口腔科学会九州地方部会
• [Presentation] Effect of bone matrix protein osteocalcin on proliferation and neuronal differentiation of PC12 cells (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] 脂肪細胞表面受容体 GPRC6A の食事誘発性肥満における役割 (2020)
  • Author(s): 溝上顕子、大谷崇仁、松田美穂、安河内(川久保)友世、竹内弘、自見英治郎、平田雅人
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] Effect of acetaminophen on TRPV4 (2019)
  • Author(s): 中川 文雄, 安藤 瑛香, 東 泉, 大住 伴子, 渡邉 誠之, 竹内 弘
  • Organizer: 第66回日本麻酔科学会学術集会
• [Presentation] 骨基質オステオカルシンによる膵α細胞の性状変化 (2019)
  • Author(s): 東泉、溝上顕子、大住伴子、平田雅人、竹内弘
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 細胞外糖濃度によるマクロファージ極性化の調節 (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、中島啓介、竹内弘
  • Organizer: 第71回日本薬理学会西南部会
• [Presentation] TRPV4に対するアセトアミノフェンの作用 (2018)
  • Author(s): 中川文雄、東泉、大住伴子、渡邉誠之、竹内弘
  • Organizer: 第71回日本薬理学会西南部会
• [Presentation] TRPV4 channel as a novel molecular target for acetaminophen (2018)
  • Author(s): Nakagawa, F., Higashi, S., Ando, E., Ohsumi, T., Watanabe, S., Takeuchi H.
  • Organizer: The 11th Japan-Korea Joint Symposium on Bio-microsensing Technology, Kitakyushu
  • Int'l Joint Research
• [Presentation] 培地グルコース濃度はAMPKを介してマクロファージ極性化に影響する (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、竹内弘
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] アセトアミノフェンはTRPV4カルシウムチャネルを抑制する (2018)
  • Author(s): 中川文雄、東泉、大住伴子、渡邉誠之、竹内弘
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] マクロファージ極性化におけるグルコース濃度の影響 (2018)
  • Author(s): 工藤崇裕、臼井通彦、竹内弘、中島啓介
  • Organizer: 日本歯周病学会
• [Presentation] 培地グルコース濃度がマクロファージの性質に与える影響について (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、中島啓介
  • Organizer: 第78回九州歯科学会
• [Presentation] アセトアミノフェンのTRPV4カルシウムチャネルに対する作用の検討 (2018)
  • Author(s): 中川文雄、東泉、大住伴子、渡邉誠之、竹内弘
  • Organizer: 第78回九州歯科学会
• [Presentation] Effect of extracellular glucose concentration on macrophage polarization. (2018)
  • Author(s): Kudo, T., Usui, M., Higashi, S., Ohsumi, T., Nakashima, K., Takeuchi, H.
  • Organizer: Asia-pacific Conference in Fukuoka 2018
  • Int'l Joint Research
• [Presentation] Modulation of TRPV4 channel activity by acetaminophen. (2018)
  • Author(s): Nakagawa, F., Higashi, S., Ohsumi, T., Watanabe, S., Takeuchi, H.
  • Organizer: Asia-pacific Conference in Fukuoka 2018
  • Int'l Joint Research
• [Presentation] 膵α細胞のホルモン分泌に対するオステオカルシンの効果 (2017)
  • Author(s): 東泉、溝上顕子、大住伴子、平田雅人、竹内弘
  • Organizer: 第90回日本薬理学会年会
• [Presentation] セレコキシブによる骨形成シグナルの抑制は、シクロオキシゲナーゼ活性に非依存的である (2017)
  • Author(s): 松山篤史、鷲尾絢子、諸冨孝彦、北村知昭、竹内弘
  • Organizer: 九州歯科学会
• [Presentation] Acetaminophen inhibits TRPV4 channel activation. (2017)
  • Author(s): Nakagawa, F., Higashi, S., Ohsumi, T., Watanabe, S., Takeuchi, H.
  • Organizer: The 66th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research
• [Presentation] Effect of acetaminophen on TRPV4 calcium channel. (2017)
  • Author(s): Nakagawa, F., Higashi, S., Ohsumi, T., Watanabe, S., Takeuchi, H.
  • Organizer: The 10th Japan-Korea Joint Symposium on Bio-microsensing Technology
  • Int'l Joint Research
• [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、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（ConBio2017）
• [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（ConBio2017）
• [Remarks] 九州歯科大学 口腔応用薬理学分野 Web ページ
  • URL: https://www.kyu-dent.ac.jp/research/lecture/oral_pharmacological
• [Remarks] 九州歯科大学 口腔応用薬理学分野 Web ページ
  • URL: https://www.kyu-dent.ac.jp/research/lecture/oral_pharmacological