Investigation in the pathogenesis of metabolic syndrome with in vivo molecular imaging

• Project/Area Number: 23591298
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: YAMASHITA Hiroshi 東京大学, 医学部附属病院, 講師 (50323572)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: メタボリックシンドローム / 生体分子イメージング / 慢性炎症 / 肥満 / 制御性B細胞 / インターロイキン１０ / 脂肪組織 / 分子イメージング / 共焦点顕微鏡 / メタボリック症候群 / 免疫異常 / リモデリング / 糖尿病

Research Abstract

Obesity is known to induce local inflammation within adipose tissue that contributes to systemic metabolic abnormalities. We investigated the underlying mechanisms that modulate adipose inflammation. We identified Breg cells that produce interleukin-10 constitutively within adipose tissue. B cell-specific Il10 deletion enhanced adipose inflammation and insulin resistance in diet-induced obese mice, whereas adoptive transfer of adipose tissue Breg cells ameliorated those effects. Adipose environmental factors, including CXCL12 and free fatty acids, support Breg cell function, and Breg cell fraction and function were reduced in adipose tissue from obese mice and humans. Our findings indicate that adipose tissue Breg cells maintain homeostasis within adipose tissue and that Breg cell dysfunction contributes pivotally to the progression of adipose tissue inflammation in obesity and may play significant roles in the pathogenesis of metabolic syndrome.

Research Products

• [Journal Article] Adipose natural regulatory B cells negatively control adipose tissue inflammation (2013)
  • Author(s): Nishimura S, Manabe I, Takaki S, Nagasaki M, Otsu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R
  • Journal Title: Cell Metab Volume: (Epub ahead of print)(PMID : 24209772)
• [Journal Article] Adipose natural regulatory B cells negatively control adipose tissue inflammation (2013)
  • Author(s): Nishimura S, Manabe I, Takaki S, Nagaskai M, Ostu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R
  • Journal Title: Cell Metabolism Volume: 18 Issue: 5 Pages: 759-766
  • DOI: 10.1016/j.cmet.2013.09.017
  • Peer Reviewed
• [Journal Article] In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling (2012)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, Kakuta S, Iwakura Y, Takayama N, Ooehara J, Otsu M, Kamiya A, Petrich BG, Urano T, Kadono T, Sato S, Aiba A, Yamashita H, Sugiura S, Kadowaki T, Nakauchi H, Eto K, Nagai R
  • Journal Title: Blood Volume: 119(PMID 22096246)
• [Journal Article] In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling. (2012)
  • Author(s): Nishimura S, Manabe I, Nagasaki M, Yamashita H, Sugiura S, Kadowaki T, Nakauchi H, Eto K, Nagai R. and et al.
  • Journal Title: Blood Volume: 119
  • Peer Reviewed
• [Journal Article] In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling (2011)
  • Author(s): S.Nishimura
  • Journal Title: Blood Volume: 119 Issue: 8 Pages: 128-131
  • DOI: 10.1182/blood-2011-09-381400
  • Peer Reviewed
• [Presentation] Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation Associated with Obesity (2013)
  • Author(s): Nisimura S, Nagasaki M, Manabe I, Eto K, Yamashita H, Komuro I, Nagai R
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜(Featured Reserach Session)
• [Presentation] Autotaxin Contributes to the Adipose Tissue Expansion and Inflammation in Diet-induced-obesity in Mice (2013)
  • Author(s): Nagasaki M, Nishimura S, Manabe I, Uno K, Yamashita H, Nagai R, Komuro I
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation Associated with Obesity (Featured Reserach Session) (2013)
  • Author(s): Nisimura S, Nagasaki M, Manabe I, Eto K, Yamashita H, Komuro I, Nagai R
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Adipose Tissue Remodeling and Malfunctioning in Obesity Associated with Chronic Inflammation and Local Immunity (2012)
  • Author(s): Nishimura S, Ngasaki M, Manabe I, Eto K, Yamashita H, Nagai R
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
• [Presentation] In Vivo Imaging Visualizes Discoid Platelet Aggregations without Endothelium Disruption and Contribution of Inflammatory Cytokine and Integrin Signaling (2012)
  • Author(s): Nishimura S, Ngasaki M, Manabe I, Eto K, Yamashita H, Nagai R
  • Organizer: 第76回日本循環器学会学術集会
  • Place of Presentation: 福岡
• [Presentation] Adipose Tissue Remodeling and Malfunctioning in Obesity Associated with Chronic Inflammation and Local Immunity (2012)
  • Author(s): Nishimura S, Ngasaki M, Manabe I, Eto K, Nagai R
  • Organizer: 日本循環器学会
  • Place of Presentation: 福岡
• [Presentation] In Vivo Imaging Visualizes Discoid Platelet Aggregations without (2012)
  • Author(s): Nishimura S, Ngasaki M, Manabe I, Eto K, Nagai R
  • Organizer: 日本循環器学会
  • Place of Presentation: 福岡
• [Presentation] Adipose Tissue Remodeling and Malfunctioning in Obesity Based on Chronic Inflammation and Abnormal Local Immunity (2011)
  • Author(s): Nishimura S, Nagasaki M, Manabe I, Eto K, Yamashita H, Nagai R
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] In Vivo Molecular Imaging Reveals Multi-cellular Kinetics of Developing Thrombus (2011)
  • Author(s): Nishimura S, Nagasaki M, Manabe I, Eto K, Yamashita H, Nagai R
  • Organizer: 第75回日本循環器学会学術集会
  • Place of Presentation: 横浜(Featured Research Session)