Effect of obesity and diabetes on liver cancer and tumor-associated macrophage polarization

• Project/Area Number: 25461333
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Toyama
• Principal Investigator: USUI Isao 富山大学, 大学病院, 講師 (50377272)
• Co-Investigator(Kenkyū-buntansha): HAYAKAWA Yoshihiro 富山大学, 和漢医薬学総合研究所, 准教授 (10541956)
• Co-Investigator(Renkei-kenkyūsha): TSUNEYAMA Koichi 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (10293341)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 肝がん / 肥満 / 糖尿病 / マクロファージ / HIF-1a / 低酸素 / HIF-1 / 肝細胞がん / 腫瘍関連マクロファージ

Outline of Final Research Achievements

In this study, the effect of high fat diet (HFD)-induced obesity and/or diabetes mellitus on liver cancer and tumor-associated macrophages (TAMs) was examined. Model mice for liver cancer were generated by intraperitoneally injecting dimethylnitrosamine (DEN), a chemical carcinogen. HFD treatment increased the number and the size of DEN-induced liver cancers, as well as the number of macrophages inside or outside of the cancers.
In macrophage-specific HIF-1a knockout mice (KO), the expression levels of both M1 and M2 activation markers were decreased in macrophages separated from the liver. Interestingly, the number of liver cancers was decreased in the KO mice, although their size was not affected, comparedwithe the wild type mice. These results suggest that TAMs, which were activated in HIF-1a-dependent manor, may promote carcinogenesis in the liver of HFD-fed mice.

Research Products

• [Journal Article] Deletion of SIRT1 in myeloid cells impairs glucose metabolism with enhancing inflammatory response to adipose tissue hypoxia (2016)
  • Author(s): Akiko Takikawa, Isao Usui , Shiho Fujisaka, Masashi Ikutani, Satoko Senda, Shinpei Hattori, Koichi Tsuneyama, Yukiko Koshimizu, Ran Inoue, Ayumi Tanaka-Hayashi, Takashi Nakagawa, Yoshinori Nagai, Kiyoshi Takatsu, Toshiyasu Sasaoka, Hisashi Mori, Kazuyuki Tobe
  • Journal Title: Diabetology International Volume: 7 Issue: 1 Pages: 59-68
  • DOI: 10.1007/s13340-015-0213-3
  • NAID: 40020774323
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adipose Tissue Hypoxia Induces Inflammatory M1 Polarity of Macrophages in HIF-1a-Dependent and HIF-1a-Independent Manners in Obese Mice. (2013)
  • Author(s): Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K..
  • Journal Title: Diabetologia Volume: 56(6) Issue: 6 Pages: 1403-1412
  • DOI: 10.1007/s00125-013-2885-1
  • Peer Reviewed
• [Journal Article] Impact of divergent effects of astaxanthin on insulin signaling in L6 cells (2013)
  • Author(s): Ishiki M, Nishida Y, Ishibashi H, Wada T, Fujisaka S, Takikawa A, Urakaze M, Sasaoka T, Usui I, Tobe K.
  • Journal Title: Endocrinology Volume: 154(8) Issue: 8 Pages: 2600-2612
  • DOI: 10.1210/en.2012-2198
  • Peer Reviewed
• [Journal Article] PACAP Attenuates NMDA-Induced Retinal Damage in Association with Modulation of the Microglia/Macrophage Status into an Acquired Deactivation Subtype. (2013)
  • Author(s): Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Tsuchida M, Yoshikawa A, Matkovits A, Kagami N, Imai N, Fujisaka S, Usui I, Tobe K, Koide R, Takahashi H, Shioda S
  • Journal Title: J Mol Neurosci. Volume: 51(2) Issue: 2 Pages: 493-502
  • DOI: 10.1007/s12031-013-0017-5
  • Peer Reviewed
• [Journal Article] Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma. (2013)
  • Author(s): Ichikawa T, Hayashi R, Suzuki K, Imanishi S, Kambara K, Okazawa S, Inomata M, Yamada T, Yamazaki Y, Koshimizu Y, Miwa T, Matsui S, Usui I, Urakaze M, Matsuya Y, Sasahara M, Tobe K.
  • Journal Title: Respirology Volume: １８ Issue: 2 Pages: 332-339
  • DOI: 10.1111/j.1440-1843.2012.02284.x
  • Peer Reviewed
• [Presentation] 肥満における脂肪組織マクロファージの機能 (2015)
  • Author(s): 薄井勲，瀧川章子, 戸辺一之
  • Organizer: 第36回日本肥満学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] Myeloid Cell-specific HIF-1 alpha Deletion Protected against Insulin Resistance with Increased Angiogenesis in High Fat-fed Mice (2015)
  • Author(s): Takikawa A, Mahmood A, Nawaz A, Kado T, Senda S, Okabe K, Usui I, Tobe K.
  • Organizer: the American Diabetes Association's 75th Scientific Sessions
  • Place of Presentation: 米国 ボストン市
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] マクロファージSIRT1による糖代謝制御 (2015)
  • Author(s): 薄井勲，瀧川章子, 戸辺一之
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関市
  • Year and Date: 2015-05-21
  • Invited
• [Presentation] マ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): 4.瀧川章子，Arshad Mahmood，Allah Nawaz，角朝信，山本誠士，常山幸一，岡部圭介，仙田聡子，中川崇，薄井勲，合田亘人，戸辺一之
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関市
  • Year and Date: 2015-05-21
• [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): 3.瀧川章子，Arshad Mahmood，Allah Nawaz，角朝信，仙田聡子，薄井勲，合田亘人，戸辺一之
  • 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
• [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，Mahmood A，薄井勲，戸邉一之
  • Organizer: 日本内分泌学会第32回内分泌代謝学サマーセミナー
  • Place of Presentation: 山梨
  • Year and Date: 2014-07-10 – 2014-07-12
• [Presentation] Myeloid Cell-Specific Deletion of Hypoxia-Inducible Factor 1-alpha Gene Protected against Diet-Induced Insulin Resistance in Mice. (2014)
  • Author(s): Takikawa A, Mahmood A, Fujisaka S, Nakagawa T, Senda S, Aminuddin A, Usui I, Tobe K.
  • Organizer: 74th scientific sessions of American Diabetes Association
  • Place of Presentation: San Francisco
  • Year and Date: 2014-06-13 – 2014-06-17
• [Presentation] 肥満脂肪組織の慢性炎症と低酸素シグナル (2014)
  • Author(s): 薄井 勲、瀧川章子、戸辺一之
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [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，薄井勲，藤坂志帆，Mahmood A，仙田聡子，Aminuddin，岡部圭介，角朝信，小清水由紀子，戸辺一之
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Depletion of CD206-positive cells is associated with increased white adipose tissue proliferation. (2014)
  • Author(s): Aminuddin, Takikawa A, Usui I, Fujisaka S, Mahmood A, Nawaz A, Tobe K
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Myeloid-Specific deletion of Hypoxia-inducible factor 1-alpha gene protected against Diet induced Insulin resistance. (2014)
  • Author(s): 9.Mahmood A, Senda S, Nakagawa T, Fujisaka S, Takikawa A, Aminuddin A, Nawaz A, Usui I, Tobe K
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-05-22 – 2014-05-24
• [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，Mahmood A，藤坂志帆，仙田聡子，Aminuddin，中川崇，薄井勲，戸邉一之
  • Organizer: 第51回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-12
• [Presentation] 脂肪組織低酸素とインスリン抵抗性 (2013)
  • Author(s): 薄井勲、藤坂志帆, 瀧川章子、Arshad Mahmood、戸辺一之
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] Myeloid cell-specific deletion of SIRT1 enhanced inflammatory response to hypoxia with glucose intolerance (2013)
  • Author(s): Akiko Takikawa, Isao Usui, Satoko Senda, Shiho Fujisaka, Yukiko Koshimizu, Koichi Tsuneyama, Amiuddin, Arshad Mahmood, Masashi Ikutani, Yoshinori Nagai, Kiyoshi Takatsu, Hisashi Mori, Kazuyuki Tobe
  • Organizer: The American Diabetes Association's 73rd Scientific Sessions
  • Place of Presentation: Chicago
  • Invited
• [Presentation] Adipose Tissue Hypoxia Induces Inflammatory M1 Polarity of Macrophages in HIF-1a -Dependent and HIF-1a Independent Manners in Obese Mice. (2013)
  • Author(s): Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, and Tobe K
  • Organizer: The American Diabetes Association's 73rd Scientific Sessions
  • Place of Presentation: Chicago
  • Invited
• [Presentation] Depletion of Cd206-positive cells is associated with increased WAT proliferation and improved insulin sensitivity. (2013)
  • Author(s): Aminuddin, Shiho Fujisaka, Hisashi Mori, Kenji Kohno, Isao Usui, Kazuyuki Tobe.
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 骨髄球特異的なHif-1α遺伝子の欠損は糖代謝を改善する (2013)
  • Author(s): マハムド アルシャド, 薄井勲, 仙田聡子, 藤坂志帆, 瀧川章子, Aminuddin, 中川崇, 戸邉一之
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Book] 医学のあゆみ (2016)
  • Author(s): 薄井 勲，戸邉一之
  • Total Pages: 4
  • Publisher: 医歯薬出版株式会社
• [Book] 月刊糖尿病 (2015)
  • Author(s): 瀧川章子，薄井 勲，戸邉一之
  • Total Pages: 8
  • Publisher: 医学出版
• [Book] Annual Review糖尿病・内分泌2014 (2014)
  • Author(s): 薄井 勲、戸辺一之
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] 血管医学 (2014)
  • Author(s): 薄井 勲、戸辺一之
  • Total Pages: 8
  • Publisher: メディカルレビュー社
• [Book] 医学のあゆみ (2014)
  • Author(s): 薄井 勲、戸辺一之
  • Total Pages: 4
  • Publisher: 医歯薬出版株式会社