HIF-1 alpha, a hypoxia inducible transcription factor, in macrophage promotes onset of insulin resistance and diabetes

• Project/Area Number: 24790918
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: University of Toyama
• Principal Investigator: SENDA Satoko 富山大学, 大学病院, 短時間勤務医師 (40597770)
• Project Period (FY): 2013-02-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 糖尿病 / 低酸素 / HIF-１α / マクロファージ / HIF-1α

Outline of Final Research Achievements

Chronic inflammation is a pathophysiology of insulin resistance in obesity. Adipose tissue macrophages play important roles in this inflammatory process. Adipose tissue becomes hypoxic as obesity progresses. We investigated the role of hypoxia-inducible factor (HIF)-1α, a key factor to hypoxic conditions, in myeloid cells using myeloid cell-specific Hif-1α knockout mice (HIF-1α KO).　High-fat-diet(HFD) fed HIF-1α KO mice showed improved glucose tolerance and improved insulin sensitivity compared to HFD fed control mice. Inflammatory change was reduced in WAT of HIF-1α KO mice. Angiogenesis was improved and hypoxia was less in WAT of HIF-1α KO mice than in WAT of control mice. In conclusion, HIF-1α in myeloid cells contributes to the development of insulin resistance with inducing inflammatory response and suppressing angiogenesis mediated by adipose tissue hypoxia.

Research Products

• [Journal Article] Calorie restriction-mediated restoration of hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation is not effective for lowering the body weight set point in IRS-2 knockout obese mice (2015)
  • Author(s): Senda S, Inoue A, Mahmood A, Suzuki R, Kamei N, Kubota N, Watanabe T, Aoyama M, Nawaz A, Ohkuma Y, Tsuneyama K, Koshimizu Y, Usui I, Saeki K, Kadowaki T and Tobe K.
  • Journal Title: Diabetology International Volume: 6 Issue: 4 Pages: 321-335
  • DOI: 10.1007/s13340-015-0205-3
  • NAID: 40020684042
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of SIRT1 in Myeloid Cells Impairs Glucose Metabolism with Enhancing Inflammatory Response to Adipose Tissue Hypoxia (2015)
  • Author(s): Takikawa A, Usui I, Fujisaka S, Ikutani M, Senda S, Hattori S, Tsuneyama K, Koshimizu Y, Inoue R, Tanaka-Hayashi A, Nakagawa T, Nagai Y, Takatsu K, Sasaoka T, Mori H, TobeK.
  • Journal Title: Diabetology International Volume: 未定
  • NAID: 40020774323
  • Peer Reviewed
• [Presentation] Myeloid Cell-specific HIF-1 Deletion Protected against Insulin Resistance with Increased Angiogenesis in High Fat-fed Mice (2015)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: American Diabetes Association’s 75th Scientific Sessions （第75回アメリカ糖尿病学会学術集会）
  • Place of Presentation: ボストン
  • Year and Date: 2015-06-05 – 2015-06-09
• [Presentation] クロファージ特異的HIF-1α欠損による食餌性肥満マウスの糖代謝・脂肪組織への影響 (2015)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関
  • Year and Date: 2015-05-21 – 2015-05-23
• [Presentation] マクロファージ特異的HIF-1α欠損は高脂肪食負荷マウスの糖代謝を改善する (2015)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] マクロファージ特異的HIF-1α欠損は高脂肪食負荷マウスの糖代謝を改善する (2014)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: 日本肥満学会第19回アディポサイエンス・シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2014-08-23
• [Presentation] 脂肪組織の慢性炎症における低酸素とマクロファージの関連 (2014)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
• [Presentation] Myeloid Cell-Specific Deletion of Hypoxia-Inducible Factor 1-alpha Gene Protected against Diet-Induced Insulin Resistance in Mice (2014)
  • Author(s): 瀧川章子、仙田聡子
  • Organizer: 第74回アメリカ糖尿病学会学術集会
  • Place of Presentation: サンフランシスコ