Novel roles of insulin and adipose tissue macrophages in fat accumulation

• Project/Area Number: 18K19554
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Gunma University
• Principal Investigator: Izumi Tetsuro 群馬大学, 生体調節研究所, 教授 (00212952)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 脂肪細胞 / マクロファージ / 脂肪蓄積 / 脂肪分解 / アディポサイトカイン / 脂肪組織マクロファージ / 脂肪代謝

Outline of Final Research Achievements

Previous genetic studies in mice have shown that functional loss of activin receptor-like kinase 7 (ALK7) increases lipolysis to resist fat accumulation in adipocytes. However, it was unknown what kind of ALK7 ligand functions or where and how its production is regulated. Here, we show that growth/differentiation factor 3 (GDF3) is a physiological ALK7 ligand under nutrient-excess conditions, and that GDF3 is produced from adipose tissue macrophages (ATMs). Furthermore, a low level of insulin upregulates in ATMs, and directs ALK7-dependent accumulation of fat in vivo. However, depletion of ATMs or transplantation of GDF3-deficient bone marrow negates the in vivo effects of insulin on both lipolysis and fat accumulation. When this insulin-GDF3-ALK7 signaling pathway is inhibited, fat weight and serum leptin levels were markedly reduced in obese mouse models. Thus, ALK7 that targets fat accumulation is promising and robust medical intervention regardless of the cause of obesity.

Academic Significance and Societal Importance of the Research Achievements

近年、生活習慣の変化により、肥満およびそれに付随する疾患の頻度が、世界レベルで急増している。肥満の成因は、遺伝要因と後天要因（環境要因）が多角的に関与しており、原因によらない、普遍的な治療法が求められるが、有効な手段がないのが現状である。本研究では、脂肪細胞における脂肪蓄積の新奇分子機構を明らかにし、また、これを抑制することにより、少なくともマウス個体レベルにおいて肥満を大幅に軽減することができることを示した。すなわち、肥満の最終表現型である脂肪蓄積を制御することにより、原因によらない肥満治療の標的と治療効果を提示し、将来のヒト肥満症への適用が期待される。

Research Products

• [Int'l Joint Research] Acceleron Pharma社(米国)
• [Journal Article] Exophilin-5 regulates allergic airway inflammation by controlling IL-33-mediated Th2 responses. (2020)
  • Author(s): Okunishi K, Wang H, Suzukawa M, Ishizaki R, Kobayashi E, Kihara M, Abe T, Miyazaki J, Horie M, Saito A, Saito H, Nakae S, and Izumi T.
  • Journal Title: J. Clin. Invest. Volume: in press
  • Peer Reviewed
• [Journal Article] Coixol amplifies glucose-stimulated insulin secretion via cAMP mediated signaling pathway. (2019)
  • Author(s): Hameed A, Hafizur RM, Kahn MI, Jawed A, Wang H, Zhao M, Matsunaga K, Izumi T, Siddiqui S, Khan F, Adhikari A, and Sharma KR.
  • Journal Title: Eur. J. Pharmacol. Volume: 858 Pages: 172514-172514
  • DOI: 10.1016/j.ejphar.2019.172514
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] インスリン、脂肪組織マクロファージを介する新奇脂肪蓄積機構 (2019)
  • Author(s): 泉 哲郎
  • Journal Title: 肥満研究 Volume: 25 Pages: 128-133
• [Journal Article] Insulin regulates lipolysis and fat mass in adipocytes by upregulating growth/differentiation factor 3 in adipose macrophages. (2018)
  • Author(s): Bu Y, Okunishi K, Yogosawa S, Mizuno K, Irudayam MJ, Brown CW, and Izumi T
  • Journal Title: Diabetes Volume: 67 Issue: 9 Pages: 1761-1772
  • DOI: 10.2337/db17-1201
  • Peer Reviewed
• [Journal Article] Response to comment on Bu et al.: Insulin regulates lipolysis and fat mass in adipocytes by upregulating growth/differentiation factor 3 in adipose macrophages. (2018)
  • Author(s): Izumi T
  • Journal Title: Diabetes Volume: 67 Issue: 12 Pages: e2-e3
  • DOI: 10.2337/dbi18-0037
  • Peer Reviewed
• [Presentation] ALK7中和抗体が肥満マウスの白色脂肪組織に及ぼす効果の検討 (2020)
  • Author(s): 奥西 勝秀、趙 敏、歩 云、泉 哲郎
  • Organizer: 第34回日本糖尿病・肥満動物学会年次学術集会
• [Presentation] メラノフィリンは開放型シンタキシン-4との結合を介して細胞膜ドッキングを迂回するインスリン開口放出を制御する (2020)
  • Author(s): 水野 広一、王 昊、奥西 勝秀、泉 哲郎
  • Organizer: 第34回日本糖尿病・肥満動物学会年次学術集会
• [Presentation] Rab27エフェクターexophilin-5のアレルギー性気道炎症における新奇の役割の解明 (2019)
  • Author(s): 奥西 勝秀、王 昊、泉 哲郎
  • Organizer: 第56回日本臨床分子医学会
• [Presentation] リポタンパク質の分泌を制御するSFT-4/Surf4 ファミリータンパク質の発見とその機能解析 (2019)
  • Author(s): 三枝 慶子、佐藤 美由紀、諸岡 信克、原 太一、松永 耕一、泉 哲郎、佐藤 健
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] Coixol amplifies glucose stimulated insulin secretion through cAMP-PKA signaling cascade-independent of K-ATP Channels. (2019)
  • Author(s): Abdul Hameed, Rahman M Hafizur, M Israr Khan, Hao Wang, Miaomiao Zhao, Kohichi Matsunaga, Tetsuro Izumi, Sonia Siddiqui, Faisal Khan, Achyut Adhikari, and Khaga Raj Sharma.
  • Organizer: The 11th Scientific Meeting of the Asian Association for the Study of Diabetes.
  • Int'l Joint Research
• [Presentation] 脂肪蓄積における白色脂肪織マクロファージの役割 (2019)
  • Author(s): 奥西 勝秀、歩 云、泉 哲郎
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] Hymecromone potentiates glucose-stimulated insulin secretion through cAMP-PKA signaling pathway. (2019)
  • Author(s): Rahman M Hafizur, M Israr Khan, Abdul Hameed, Kiran Maryam, Huma Aslam Bhatti, Munneb Ali, Zaheer-UI, Faisal Khan, Ghulam Abbas, Hao Wang, Kohichi Matsunaga, and Tetsuro Izumi.
  • Organizer: 第62回日本糖尿病学会年次学術集会
• [Presentation] Rab27エフェクターexophilin-5のアレルギー反応における役割 (2019)
  • Author(s): 奥西 勝秀、王 昊、泉 哲郎
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] Exocytosis of insulin granules captured within the actin cortex. (2019)
  • Author(s): Tetsuro Izumi
  • Organizer: BDI Diabetes Forum
  • Int'l Joint Research / Invited
• [Presentation] Melanophilin accelerates insulin granule fusion without stable docking to the plasma membrane via interaction with myosin-Va and syntaxin-4. (2019)
  • Author(s): Tetsuro Izumi, Kouichi Mizuno, Katsuhide Okunishi, and Hao Wang
  • Organizer: The 55th Annual Meeting of the EASD
  • Int'l Joint Research
• [Presentation] ALK7中和抗体の投与は肥満マウスの脂肪重量を著減させる (2019)
  • Author(s): 奥西 勝秀、歩 云、趙 敏、泉 哲郎
  • Organizer: 第40回日本肥満学会
• [Presentation] Huma Aslam Bhatti. Exploring the insulin secretory mechanisms of hymecromone and eupatorin in mice islets. (2019)
  • Author(s): Rahman M Hafizur, Abdul Hameed, M Israr Khan, Kiran Maryam, Muneeb Ali, Za-heer Ul-Haq, Hao Wang, Miaomiao Zhao, Kohichi Matsunaga, Tetsuro Izumi, Achyut Adhi-kari
  • Organizer: The 7th International Symposium-cum-Training Course on Molecular Medicine and Drug Research, Karachi, Pakistan
  • Int'l Joint Research
• [Presentation] ALK7中和抗体による脂肪減量効果の検討 (2019)
  • Author(s): 趙 敏、歩 云、奥西 勝秀、泉 哲郎
  • Organizer: 第5回生体調節研究所内分泌代謝シンポジウム
• [Presentation] A novel regulatory role of the Rab27 effector exophilin5 in allergic airway inflammation. (2019)
  • Author(s): Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Susumu Nakae, and Tetsuro Izumi
  • Organizer: 第48回日本免疫学会
• [Presentation] インスリンのALK7依存的な脂肪蓄積作用の解明 (2019)
  • Author(s): 奥西 勝秀、歩 云、泉 哲郎
  • Organizer: 第33回日本糖尿病・肥満動物学会年次学術集会
• [Presentation] 糖尿病・肥満を呈するマウスの遺伝学的解析。平成31年糖尿病・肥満動物学会学会賞「米田賞」受賞講演 (2019)
  • Author(s): 泉 哲郎
  • Organizer: 第33回日本糖尿病・肥満動物学会年次学術集会
  • Invited
• [Presentation] Insulin regulates lipolysis and fat mass by upregulating growth/differentiation factor 3 in adipose tissue macrophages. (2018)
  • Author(s): Tetsuro Izumi, Yun Bu, and Katsuhide Okunishi
  • Organizer: EASD 2018
  • Int'l Joint Research
• [Presentation] マクロファージを介する、インスリンの新奇脂肪蓄積作用（シンポジウム、肥満脂肪組織病態学の最先端）。 (2018)
  • Author(s): 泉 哲郎
  • Organizer: 第39回日本肥満学会
  • Invited
• [Presentation] Adipose tissue macrophages promote adiposity by suppressing lipolysis in white adipocytes through activation of the GDF3-ALK7 axis. (2018)
  • Author(s): Katsuhide Okunishi, Yun Bu, and Tetsuro Izumi
  • Organizer: 第47回日本免疫学会
• [Remarks] 喘息重症化の抑制機構の解明 ～エキソフィリン5が喘息の重症化を防ぐ
  • URL: https://www.imcr.gunma-u.ac.jp/?p=7861
• [Remarks] 群馬大学生体調節研究所遺伝生化学分野
  • URL: http://molend.showa.gunma-u.ac.jp/