Amelioration of adipose inflammation and insulin resistance in aged and diet-induced obese mice by targeting programmed death-1+ adipose T cells

• Project/Area Number: 25461116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Hyogo Medical University (2014-2015); Keio University (2013)
• Principal Investigator: Shinmura Ken 兵庫医科大学, 医学部, 教授 (70206332)
• Research Collaborator: FUKUDA KEIICHI 慶應義塾大学, 医学部, 教授 (20199227) ; SANO MOTOAKI 慶應義塾大学, 医学部, 准教授 (30265798) ; ENDO JIN 慶應義塾大学, 医学部, 助教 (50398608)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 免疫老化 / 炎症 / T細胞 / インスリン抵抗性 / 肥満 / 脂肪細胞 / 抗体治療 / マクロファージ / 脂肪組織

Outline of Final Research Achievements

Obesity is associated with accelerated biological aging and predisposes to the early onset of aging-related diseases. We investigate the mechanisms of how obesity accelerates aging. Diet-induced and age-related adiposity were associated with an accumulation of Programmed Death-1(PD-1)+ memory phenotype(MP) CD4+ T cells having features of senescence in visceral adipose tissue(VAT). The PD-1+ MP CD4+ T cells stimulated macrophage infiltration and promoted M1 macrophage polarization, while reducing regulatory T cells in VAT. Immunological depletion of PD-1+ T cells attenuated adipose inflammation and improved insulin resistance in diet-induced obese mice, while adoptive transfer of PD-1+ MP CD4+ T cells in VAT induced adipose inflammation and insulin resistance in non-obese mice. Adipose macrophages was involved in the development of PD-1+ MP CD4+ T cells. We proposed that T cell senescence originating in VAT contributes to the mechanism of how obesity causes aging.

Research Products

• [Journal Article] Cardiac Senescence, Heart Failure, and Frailty: A Triangle in Elderly People (2016)
  • Author(s): Shinmura K.
  • Journal Title: The Keio Journal of Medicine Volume: 65 Issue: 2 Pages: 25-32
  • DOI: 10.2302/kjm.2015-0015-IR
  • NAID: 130005158313
  • ISSN: 0022-9717, 1880-1293
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia/reperfusion. (2016)
  • Author(s): Yamamoto T, Tamaki K, Shirakawa K, Ito K, Yan X, Katsumata Y, Anzai A, Matsuhashi T, Endo J, Inaba T, Tsubota K, Sano M, Fukuda K, Shinmura K,
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 310 Issue: 8 Pages: H1003-H1014
  • DOI: 10.1152/ajpheart.00676.2015
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Obesity accelerates T cell senescence in visceral adipose tissue. (2015)
  • Author(s): Shirakawa K, Shinmura K, Endo J, Kataoka M, Yamamoto T, Katsumata Y, Anzai A, Isobe S, Yoshida N, Fukuda K ,Sano M.
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orange County Convention Center (Oralndo, FL, USA)
  • Year and Date: 2015-11-10
  • Int'l Joint Research
• [Presentation] Senescence-related T cells in visceral adipose tissue promote adipose inflammation in diet-induced obese mice. (2015)
  • Author(s): Shinmura K.
  • Organizer: 第57回日本老年医学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県、横浜市)
  • Year and Date: 2015-06-13
• [Presentation] Senescence-related T cells in visceral adipose tissue promote adiopose inflammation in diet-induced obese mice. (2015)
  • Author(s): Shinmura K.
  • Organizer: 第29回日本老年学会総会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2015-06-13
• [Presentation] Amelioration of adipose inflammation and insulin resistance in aged and diet-induced obese mice by targeting programmed death 1+ adipose T cells. (2015)
  • Author(s): Shirakawa K, Yan X, Shinmura K, Endo J, Tamaki K, Katsumata Y, Yamamoto T, Anzai A, Matsuhashi T, Fukuda K, Sano M.
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府、大阪市)
  • Year and Date: 2015-04-24
• [Presentation] Amelioration of adipose inflammation and insulin resistance in aged and diet-induced obese mice by targeting programmed death 1+ adipose T cells (2015)
  • Author(s): Shirakawa K, Yan X, Shinmura K, Endo J, Tamaki K, Katsumata Y, Yamamoto T, Anzai A, Matsuhashi T, Fukuda K, Sano M.
  • Organizer: 第79回日本循環器学会年次集会 YIA finalists講演
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Amelioration of adipose inflammation and insulin resistance by targeting programmed death 1+ adipose T cells (2014)
  • Author(s): 白川公亮、佐野元昭、遠藤 仁、玉城香代子、伊藤健太郎、山本恒久、勝俣良紀、安西 淳、松橋智弘、福田恵一、森本耕吉、渡邉光博、八木田秀雄、新村 健。
  • Organizer: 第14回日本坑加齢医学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-07
• [Presentation] Programmed death 1+ T cells integrate adipose inflammation and develop insulin resistance in aged and type 2 diabetic mice. (2014)
  • Author(s): Shirakawa K, Yan X, Sano M, Endo J, Ito K, Yamamoto T, Katsumata Y, Anzai A, Matsuhashi T, Fukuda K, Morimoto K, Watanabe M, Yagita H, Shinmura K.
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都）
• [Book] 代謝異常治療研究基金研究業績集 第41集2014 (2015)
  • Author(s): 新村 健、閂 小響、白川公亮、玉城香代子、遠藤 仁、佐野元昭、福田恵一。
  • Total Pages: 15
  • Publisher: 一般社団法人 代謝異常治療研究基金
• [Patent(Industrial Property Rights)] 加齢又は肥満に伴う慢性炎症の抑制剤、加齢又は肥満に伴う慢性炎症に関連する疾患の治療剤又は予防剤、罹患可能性評価装置及びスクリーニング方法 (2014)
  • Inventor(s): 佐野元昭、新村 健
  • Industrial Property Rights Holder: 佐野元昭、新村 健
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014