The role of M2-like macrophages in glucose metabolism

• Project/Area Number: 26461327
• 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: TOBE Kazuyuki 富山大学, 大学院医学薬学研究部(医学), 教授 (30251242)
• Co-Investigator(Kenkyū-buntansha): 瀧川 章子 富山大学, 大学院医学薬学研究部(医学), 客員助教 (80647454)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: インスリン抵抗性 / M2マクロファージ / インスリン抵抗 / マクロファージ / 炎症

Outline of Final Research Achievements

Adipose tissue resident macrophages (ATMs) play important roles in regulating insulin sensitivity via their anti-inflammatory actions. However, the mechanism by which ATMs affect the functions of adipocytes is largely unknown. Here, we show that the CD206/TGFβ pathway plays critical roles in regulating adipogenesis and glucose homeostasis. Adipose tissue CD206+ cells were determined to be exclusively M2 macrophages, and a reduction in their number improved systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. The genetically engineered CD206+cells-reduced mice showed a down-regulation of TGFβ signaling in adipose tissue, which was accompanied by up-regulated proliferation and differentiation of adipocyte progenitors (APs), thereby providing increased numbers of smaller adipocytes. Our findings indicate that CD206+ cells regulate APs’ growth/differentiation and thereby control adiposity and systemic insulin sensitivity.

Research Products

• [Journal Article] HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance. (2016)
  • Author(s): Takikawa A, Mahmood A, Nawaz A, Kado T, Okabe K, Yamamoto S, Arif A, Senda S, Tsuneyama K, Ikutani M, Watanabe Y, Igarashi Y, Nagai Y, Takatsu K, Koizumi K, Imura J, Goda N, Sasahara M, Matsumoto M, Saeki K, Nakagawa T, Fujisaka S, Usui I, Tobe K.
  • Journal Title: Diabetes Volume: 65(12) Issue: 12 Pages: 3649-3659
  • DOI: 10.2337/db16-0012
  • NAID: 40021380120
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] M2 macrophages in metabolism. (2016)
  • Author(s): Fujisaka S, Usui I, Nawaz A, Takikawa A, Kado T, Igarashi Y, Tobe K.
  • Journal Title: Diabetes Int. Volume: 7 Issue: 4 Pages: 342-351
  • DOI: 10.1007/s13340-016-0290-y
  • NAID: 40021041341
  • Peer Reviewed
• [Journal Article] Nmnat3 is not essential for the maintenance of mitochondrial NAD level in vivo. (2016)
  • Author(s): Yamamoto M, Hikosaka K, Mahmood A, Tobe K, Shojaku H, Nakagawa T
  • Journal Title: PLOS ONE Volume: 11(1) Issue: 1 Pages: e0147037-e0147037
  • DOI: 10.1371/journal.pone.0147037
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes. (2016)
  • Author(s): Imamura M, ・・Yamauchi T,・・ Shojima N, ・・Kadowaki T
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 10531-10531
  • DOI: 10.1038/ncomms10531
  • NAID: 120006889946
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FTO gene polymorphism is associated with Type 2 diabetes through its effect on increasing the maximum BMI in Japanese men. (2016)
  • Author(s): Kamura Y, Iwata M, Maeda S, Shinmura S, Koshimizu Y, Hounoki H, Fukuda K, Ishiki M, Usui I, Fukushima Y, Takano A, Kato H, Murakami S, Higuchi K, Kobashi C, Tobe K.
  • Journal Title: PLOS ONE Volume: 11(11) Issue: 11 Pages: e0165523-e0165523
  • DOI: 10.1371/journal.pone.0165523
  • Peer Reviewed / Open Access
• [Journal Article] Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways. (2016)
  • Author(s): Kubota T, Kubota N, Sato H, Inoue M, Kumagai H, Iwamura T, Takamoto I, Kobayashi T, Moroi M, Terauchi Y, Tobe K, Ueki K, Kadowaki T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34707-34707
  • DOI: 10.1038/srep34707
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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, Tobe K.
  • Journal Title: Diabetol Int. Volume: Dec;6(4) Pages: 321-35
  • Peer Reviewed / Open Access
• [Journal Article] Replication study for the association of rs7578597 in THADA, rs10886471 in GRK5 and rs7403531 in RASGRP1 with susceptibility to type 2 diabetes in a Japanese population. (2015)
  • Author(s): Sakai K, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Hirotaka Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S.
  • Journal Title: Diabetology International Volume: Dec;6(4) Pages: 306-312
  • Peer Reviewed / Open Access
• [Journal Article] Sirtuin1 maintains actin cytoskeleton by deacetylation of cortactin in injured podocytes. (2015)
  • Author(s): Motonishi S, Nangaku M, Wada T, Ishimoto Y, Ohse T, Matsusaka T, Kubota N, Shimizu A, Kadowaki T, Tobe K, Inagi R.
  • Journal Title: J Am Soc Nephrol. Volume: Aug;26(8) Pages: 1939-59
  • Peer Reviewed / Open Access
• [Journal Article] SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD(+) and Function in Mice. (2015)
  • Author(s): Yoon MJ, Yoshida M, Johnson S, Takikawa A, Usui I, Tobe K, Nakagawa T, Yoshino J, Imai S.
  • Journal Title: Cell Metab. Volume: May 5;21(5) Pages: 706-17
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes. (2015)
  • Author(s): Matsuba R, Sakai K, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S.
  • Journal Title: PLoS One. Volume: May 7;10(5)
  • Peer Reviewed / Open Access
• [Journal Article] Association of serum adiponectin with asthma and pulmonary function in the Japanese population. (2015)
  • Author(s): Hayashikawa Y, Iwata M, Inomata M, Kawagishi Y, Tokui K, Taka C, Kambara K, Okazawa S, Yamada T, Hayashi R, Kamura Y, Okazawa T, Matsui S, Kigawa M, Tobe K.
  • Journal Title: Endocr J. Volume: May 15;62(8) Pages: 695-709
  • NAID: 130005094619
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. (2015)
  • Author(s): Yoon MJ, Yoshida M, Johnson S, Takikawa A, Usui I, Tobe K, Nakagawa T, Yoshino J, Imai SI.
  • Journal Title: Cell Metabolism Volume: 21(1) Issue: 5 Pages: 1-12
  • DOI: 10.1016/j.cmet.2015.04.002
  • Peer Reviewed / Acknowledgement Compliant
• [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, Tobe K.
  • Journal Title: Diabetology International Volume: 未定
  • NAID: 40020774323
  • Peer Reviewed
• [Journal Article] Deficiency of nicotinamide mononucleotide adenylyltransferase 3 (nmnat3) causes Hemolytic anemia by altering the glycolytic flow in mature erythrocytes. (2014)
  • Author(s): Hikosaka K., Ikutani M., Shito M., Kazuma K., Gulshan M., Nagai Y., Takatsu K., Konno K., Tobe K., Kanno H., Nakagawa T.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 21 Pages: 14796-14811
  • DOI: 10.1074/jbc.m114.554378
  • Peer Reviewed
• [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． (2016)
  • Author(s): 8) 瀧川章子，Arshad Mahmood，Allah Nawaz，岡部圭介，角 朝信，中川 崇，藤坂志帆，薄井 勲，戸邉一之．
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-07
• [Presentation] 肥満症・糖尿病での肝がん発症におけるマクロファージHIF-1αの働き． (2016)
  • Author(s): 瀧川章子，薄井 勲，張 群，岡部圭介，角 朝信，Allah Nawaz，藤坂志帆，常山幸一，戸邉一之．
  • Organizer: 第34回内分泌代謝学サマーセミナー
  • Place of Presentation: 久山
  • Year and Date: 2016-07-14
• [Presentation] Myeloid cell-specific HIF-1α deletion decreases the number of liver tumors in high fat-fed mice. (2016)
  • Author(s): Takikawa A, Usui I, Zhang Q, Okabe K, Kado T, Nawaz A, Fujisaka S, Nakagawa T, Tsuneyama K, Tobe K.
  • Organizer: 76th Scientific Sessions of American Diabetes Association
  • Place of Presentation: New Orleans
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] Nampt-mediated NAD synthesis regulates the metabolic remodeling during the differentiation of 3T3-L1 pre-adipocytes. (2016)
  • Author(s): Okabe K, Usui I, Tobe K, Nakagawa T.
  • Organizer: 76th Scientific Sessions of American Diabetes Association
  • Place of Presentation: New Orleans
  • Year and Date: 2016-06-10
  • Int'l Joint Research
• [Presentation] 肥満症・糖尿病での肝がん発症におけるマクロファージHIF-1αの働き． (2016)
  • Author(s): 3) 瀧川章子，薄井 勲，張 群，岡部圭介，角 朝信，Allah Nawaz，藤坂志帆，常山幸一，戸邉一之．
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] 2型糖尿病患者の内因性インスリン分泌評価指標に及ぼす腎機能の影響. (2016)
  • Author(s): 4) 岡部圭介，岩田 実，渡邊善之，中嶋 歩，角 朝信，瀧川章子，朴木久恵，小清水由紀子，石木 学，薄井 勲，戸邉一之．
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
• [Presentation] Nampt-mediated NAD synthesis regulates the differentiation of 3T3-L1 pre-adipocytes via poly(ADP-ribosyl)ation by PARPs． (2016)
  • Author(s): 岡部圭介，薄井 勲，戸邉一之，中川 崇．
  • Organizer: 第21回アディポサイエンス・シンポジウム
  • Place of Presentation: 大阪
• [Presentation] 肥満における臓器障害－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，戸邉一之．
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-02
  • Invited
• [Presentation] The effect of renal function on β-cell function related parameters in Japanese type 2 diabetic patients. (2015)
  • Author(s): Okabe K, Iwata M, Nakashima A, Shinmura S, Kado T, Wakura T, Takikawa A, Koshimizu Y, Hounoki H, Ishiki M, Fukuda K, Usui I, Tobe K.
  • Organizer: 75th scientific sessions of American Diabetes Association
  • Place of Presentation: Boston
  • Year and Date: 2015-06-05
• [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: 75th scientific sessions of American Diabetes Association
  • Place of Presentation: Boston
  • Year and Date: 2015-06-05
• [Presentation] 老化のサイエンスSirtuin研究の深化と展望マクロファージSIRT1による糖代謝制御． (2015)
  • Author(s): 薄井 勲，瀧川章子，戸邉一之．
  • 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，Arshad Mahmood，Allah Nawaz，角 朝信，仙田聡子，薄井 勲，合田亘人，戸邉一之．
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2015-04-23
• [Presentation] マクロファージ特異的HIF-1 alpha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，Mahmood A，Nawaz A，角朝信，薄井勲，戸邉一之
  • Organizer: 第29回日本糖尿病・肥満動物学会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-13 – 2015-02-14
• [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，仙田聡子，薄井勲，戸邉一之
  • 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] 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] Astaxanthin, a strong antioxidant, ameliorated glucose metabolism in obese mouse through various mechanisms (2014)
  • Author(s): IshikiM, NishidaY, TakikawaA, KoshimizuY, IwataM, UsuiI, TobeK.
  • Organizer: 74th scientific sessions of American Diabetes Association
  • Place of Presentation: San Francisco
  • Year and Date: 2014-06-13 – 2014-06-17
• [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] 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，戸邉一之．
  • 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): 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