Role of CCR5 and CX3CR1 in the development of insulin resistance

• Project/Area Number: 22790854
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: OTA Tsuguhito 金沢大学, フロンティアサイエンス機構, 特任助教 (60397213)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 炎症 / インスリン抵抗性 / ケモカイン / 脂肪組織 / 肥満 / マクロファージ / 糖尿病 / 脂肪肝

Research Abstract

Monocyte chemoattractant protein-1(MCP-1) and its receptor CCR2 are pivotal for adipose tissue macrophage(ATM) recruitment and the development of insulin resistance. However, other chemokine systems may also play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue(WAT) of genetically(ob/ob) and high-fat(HF) diet-induced obese(DIO) mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter analysis also revealed that DIO mice had a robust increase in CCR5+cells within ATMs compared with chow-fed mice. Furthermore, Ccr5-/-mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both reduction of total ATM content and an M2 dominant shift in ATM polarization. Thus, CCR5 plays a critical role in ATM recruitment and polarization and subsequent development of insulin resistance.

Research Products

• [Journal Article] CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status (2012)
  • Author(s): Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y, Takamura T, Yamamoto H, Miyamoto K, Ginsberg HN, Mukaida N, Kaneko S, Ota T
  • Journal Title: Diabetes IN PRESS Volume: 61(7) Issue: 7 Pages: 1680-90
  • DOI: 10.2337/db11-1506
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress inhibits STAT3-dependent suppression of hepatic gluconeogenesis via dephosphorylation and deacetylation (2012)
  • Author(s): Kimura K, Yamada T, Matsumoto M, Kido Y, Hosooka T, Asahara S, Matsuda T, Ota T, Watanabe H, Sai Y, Miyamoto K, Kaneko S, Kasuga M, Inoue H
  • Journal Title: Diabetes Volume: 61 Pages: 61-73
  • Peer Reviewed
• [Journal Article] Inverse Correlation between Serum Levels of Selenoprotein P and Adiponectin in Patients with Type 2 Diabetes (2012)
  • Author(s): Misu H, Ishikura K, Kurita S, Takeshita Y, Ota T, Saito Y, Takahashi K, Kaneko S, Takamura T
  • Journal Title: PLoS One Volume: 7
  • NAID: 120004140847
  • Peer Reviewed
• [Journal Article] Different fatty acids inhibit apolipoprotein B100 secretion by different pathways : Unique roles for endoplasmic reticulum stress, ceramide, and autophagy (2011)
  • Author(s): Caviglia JM, Gayet C, Ota T, Hernandez-Ono A, Conlon DM, Jiang H, Fisher EA, Ginsberg HN
  • Journal Title: J Lipid Res Volume: 52 Pages: 1636-1651
  • Peer Reviewed
• [Journal Article] 脂肪肝の成因としての小胞体ストレスの意義,小胞体ストレスと疾患 (2011)
  • Author(s): 太田嗣人
  • Journal Title: Bio Clinica Volume: 26(7) Pages: 28-32
• [Journal Article] 慢性炎症とインスリン抵抗性をリンクするケモカインの役割,メタボリックシンドロームII(後篇)-メタボリックシンドロームの基礎-成因と病態/遺伝子・病態・標的分子の面から (2011)
  • Author(s): 太田嗣人, 篁俊成
  • Journal Title: ケモカイン最新医学 Volume: 66(6) Pages: 192-204
• [Journal Article] A liver-derived secretory protein, selenoprotein P, causes insulin resistance (2010)
  • Author(s): Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, Ishikura K, Ando H, Takeshita Y, Ota T, Sakurai M, Yamashita T, Mizukoshi E, Honda M, Miyamoto K, Kubota T, Kubota N, Kadowaki T, Kim HJ, Lee IK, Minokoshi Y, Saito Y, Takahashi K, Yamada Y, Takakura N, Kaneko S
  • Journal Title: Cell Metab Volume: 12 Pages: 483-495
  • NAID: 120002661942
  • Peer Reviewed
• [Journal Article] Effect of pioglitazone on muscle sympathetic nerve activity in type 2 diabetes mellitus with alpha-glucosidase inhibitor (2010)
  • Author(s): Kobayashi D, Takamura M, Murai H, Usui S, Ikeda T, Inomata J, Takashima S, Kato T, Furusho H, Takeshita Y, Ota T, Takamura T, Kaneko S
  • Journal Title: Auton Neurosci Volume: 158 Pages: 86-91
  • Peer Reviewed
• [Journal Article] 肝疾患における血液,脂質一般検査生化学検査の臨床的意義 (2010)
  • Author(s): 太田嗣人, 篁俊成
  • Journal Title: 肝胆膵 Volume: 60 Pages: 541-547
• [Journal Article] A liver-derived secretory protein, selenoprotein P, causes insulin resistance. (2010)
  • Author(s): Misu H
  • Journal Title: Cell Metab Volume: 12 Pages: 483-495
  • Peer Reviewed
• [Journal Article] Effect of pioglitazone on muscle sympathetic nerve activity in type 2 diabetes mellitus with alpha-glucosidase inhibitor. (2010)
  • Author(s): Kobayashi D
  • Journal Title: Auton Neurosci Volume: 158 Pages: 86-91
  • Peer Reviewed
• [Presentation] CCR5 ablation prevents insulin resistance induced by high-fat feeding or leptin deficiency (2012)
  • Author(s): Tsuguhito Ota, Hironori Kitade, Kazuki Sawamoto, Hiroshi Inoue, Toshinari Takamura, Naofumi Mukaida, Shuichi Kaneko
  • Organizer: 第16回国際動脈硬化シンポジウム
  • Place of Presentation: シドニー(オーストラリア)
  • Year and Date: 2012-03-28
• [Presentation] 肥満による炎症とインスリン抵抗性をリンクするCCR5の役割～脂肪組織マクロファージの量および質の調節への関与～ (2012)
  • Author(s): 太田嗣人1、澤本一樹1、北出紘規1、山本靖彦2、井上啓1、篁俊成3、山本博2、向田直史4、金子周一3
  • Organizer: 第26回日本糖尿病・肥満動物学会年次学術集会
  • Place of Presentation: 愛知県産業労働センター(愛知)
  • Year and Date: 2012-02-17
• [Presentation] CCR5 plays a critical role in the inflammatory adipose tissue response to obesity by regulating both macrophage recruitment and M1/M2 status (2011)
  • Author(s): Tsuguhito Ota, Kazuki Sawamoto, Hironori Kitade, Yasuhiko Yamamoto, Hiroshi Inoue, Toshinari Takamura, Ken-ichi Miyamoto, Hiroshi Yamamoto Naofumi Mukaida, Shuichi Kaneko
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-14
• [Presentation] Loss of CCR5 attenuates obesity-induced insulin resistance through M2 dominant shift in adipose tissue macrophage (2011)
  • Author(s): Tsuguhito Ota, Kazuki Sawamoto, Hironori Kitade, Yasuhiko Yamamoto, Hiroshi Inoue, Toshinari Takamura, Ken-ichi Miyamoto, Hiroshi Yamamoto Naofumi Mukaida, Shuichi Kaneko
  • Organizer: 第21回2011年国際糖尿病学会議(IDF2011)
  • Place of Presentation: ドバイ(アラブ首長国連邦)
  • Year and Date: 2011-12-08
• [Presentation] 肥満による炎症とインスリン抵抗性をリンクするCCR5の意義～脂肪組織マクロファージの量および質の調整への関与～ (2011)
  • Author(s): 太田嗣人,澤本一樹,北出紘規,山本靖彦,井上啓,篁俊成,山本博,向田直史,金子周一
  • Organizer: 第26回日本糖尿病合併症学会
  • Place of Presentation: 大宮ソニックシティ(埼玉県)
  • Year and Date: 2011-10-14
• [Presentation] CCR5の欠損はob/obマウスの脂肪組織の炎症を軽減しインスリン抵抗性を改善する (2011)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,金子周一
  • Organizer: 第32回日本肥満学会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 2011-09-24
• [Presentation] CCR5 deficiency attenuates obesity-induced insulin resistance through M2 dominant shift in adipose tissue macrophage (2011)
  • Author(s): T. Ota, K. Sawamoto, H. Kitade, Y. Yamamot o, H. Inoue, T. Takamura, H. Yamamoto, N. M ukaida, S. Kaneko
  • Organizer: 第47回欧州糖尿病学会議総会
  • Place of Presentation: 日リスボン(ポルトガル)
  • Year and Date: 2011-09-15
• [Presentation] CCR5 deficiency attenuates obesity-induced insulin resistance through M2 dominant shift in adipose tissue macrophage (2011)
  • Author(s): 太田嗣人
  • Organizer: 第47回欧州糖尿病学会議(EASD)
  • Place of Presentation: リスボン、ポルトガル
  • Year and Date: 2011-09-15
• [Presentation] CCR5 plays a critical role in the inflammatory adipose tissue response to high-fat feeding and obesity by regulating both macrophage recruitment and M1/M2 status (2011)
  • Author(s): TSUGUHITO OTA, KAZUKI SAWAMOTO, HIRONORI KITADE, YASUHIKO YAMAMOTO. HIROSHI INOUE, TOSHINARI TAKAMURA, KEN-ICHI MIYAMOTO, HIROSHI YAMAMOTO, NAOFUMI MUKAIDA, SHUICHI KANEKO
  • Organizer: 第71回アメリカ糖尿病学会
  • Place of Presentation: サンディエゴ(米国)
  • Year and Date: 2011-06-24
• [Presentation] CCR5 plays a critical role in the inflammatory adipose tissue response to high-fat feeding and obesity by regulating both macrophage recruitment and M1/M2 status (2011)
  • Author(s): 太田嗣人
  • Organizer: 第71回米国糖尿病学会(ADA)
  • Place of Presentation: サンディエゴ、米国
  • Year and Date: 2011-06-24
• [Presentation] CCR5 ablation prevents insulin resistance by high-fat feeding or leptin deficiency (2011)
  • Author(s): T Ota, H Kitade, K Sawamoto, H Inoue, T Takamura, K Miyamoto, N Mukaida, S Kaneko
  • Organizer: 日本分子生物学会第11回春季シンポジウム
  • Place of Presentation: 石川県立音楽堂(石川)
  • Year and Date: 2011-05-26
• [Presentation] CCR5欠損はob/obマウスの脂肪組織の炎症を軽減し糖代謝異常を改善する (2011)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,篁俊成,宮本謙一,向田直史,金子周一
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2011-05-21
• [Presentation] 肥満によるる脂肪組織マクロファージの量の変化と質の調節が関わるインスリン抵抗性の発症にはCCR5によ (2011)
  • Author(s): 澤本一樹,北出紘規, Ni Yinhua,山本靖彦,井上啓,篁俊成,宮本謙一,山本博,向田直史,金子周一,太田嗣人
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2011-05-21
• [Presentation] ケモカイン受容体CCR5の欠損は脂肪組織の炎症と全身のインスリン抵抗性を改善する (2011)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,篁俊成,宮本謙一,向田直史,金子周一
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2011-04-23
• [Presentation] CCR5 Ablation Prevents Insulin Resistance Induced by High-Fat Feeding or Leptin Deficiency (2010)
  • Author(s): KAZUKI SAWAMOTO, TSUGUHITO OTA, HIRONORI KITADE, HIROSHI INOUE, TOSHINARI TAKAMURA, KEN-ICHI MIYAMOTO, NAOFUMI MUKAIDA, SHUICHI KANEKO
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場(兵庫)
  • Year and Date: 2010-12-10
• [Presentation] インスリン抵抗性の形成におけるケモカイン受容体CCR5の役割 (2010)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,篁俊成,宮本謙一,向田直史,金子周一
  • Organizer: 第22回日本分子糖尿病シンポジウム
  • Place of Presentation: 東京コンファレンスセンター品川(東京)
  • Year and Date: 2010-12-04
• [Presentation] インスリン抵抗性形成におけるケモカインレセプターCCR5の役割 (2010)
  • Author(s): 北出紘規,太田嗣人,澤本一樹,井上啓,篁俊成,宮本謙一,向田直史,金子周一
  • Organizer: 第25回日本糖尿病合併症学会
  • Place of Presentation: びわ湖ホール(滋賀)
  • Year and Date: 2010-10-22
• [Presentation] CCR5 PROMOTES ADIPOSE TISSUE INFLAMMATION AND WHOLE-BODY INSULIN RESISTANCE (2010)
  • Author(s): T Ota, H Kitade, K Sawamoto, H Inoue, T Takamura, K Miyamoto, N Mukaida, S Kaneko
  • Organizer: 第8回国際糖尿病連合西太平洋地区会議
  • Place of Presentation: 釜山(韓国)
  • Year and Date: 2010-10-19
• [Presentation] 肥満による炎症とインスリン抵抗性の形成によるケモカイン受容体CCR5の重要性 (2010)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,向田直史,金子周一
  • Organizer: 第31回日本肥満学会
  • Place of Presentation: 前橋テルサ(群馬)
  • Year and Date: 2010-10-01
• [Presentation] CCR5 promotes adipose tissue inflammation and Insulin resistance in obesity (2010)
  • Author(s): Tsuguhito Ota, Hironori Kitade, Kazuki Sawamoto, Hiroshi Inoue, Shuichi Kaneko
  • Organizer: 第46回欧州糖尿病学会議
  • Place of Presentation: ストックホルム(スウェーデン)
  • Year and Date: 2010-09-23
• [Presentation] KANEKO, CCR5 Ablation Prevents Insulin Resistance Induced by High-Fat Feeding or Leptin Deficiency (2010)
  • Author(s): TSUGUHITO OTA, HIRONORI KITADE, KAZUKI SAWAMOTO, HIROSHI INOUE, TOSHINARI TAKAMURA, KEN-ICHI MIYAMOTO, NAOFUMI MUKAIDA, SHUICHI KANEKO
  • Organizer: 第70回アメリカ糖尿病学会
  • Place of Presentation: オーランド(米国)
  • Year and Date: 2010-06-27
• [Presentation] CCR5 ablation prevents insulin resistance induced by high-fat feeding or leptin deficiency (2010)
  • Author(s): 太田嗣人
  • Organizer: 米国糖尿病学会(ADA)
  • Place of Presentation: Orange County Convention Center(米国)
  • Year and Date: 2010-06-27
• [Presentation] インスリン抵抗性の形成におけるケモカインレセプターCCR5の役割 (2010)
  • Author(s): 太田嗣人,北出紘規,澤本一樹,井上啓,篁俊成,宮本謙一,向田直史,金子周一
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山全日空ホテル(岡山)
  • Year and Date: 2010-05-29
• [Book] 慢性炎症とインスリン抵抗性をリンクするケモカインの役割,メタボリックシンドロームII(後篇)-メタボリックシンドロームの基礎-成因と病態/遺伝子・病態・標的分子の面から:ケモカイン (2011)
  • Author(s): 太田嗣人
  • Total Pages: 13
  • Publisher: 最新医学66(6):192-204,2011,最新医学社
• [Remarks]
  • URL: http://ota.w3.kanazawa-u.ac.jp/