Analysis of the role of the immunoproteasome in obesity and diabetes

• Project/Area Number: 26461386
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Jichi Medical University
• Principal Investigator: Kimura Hiroaki 自治医科大学, 医学部, 講師 (70593622)
• Co-Investigator(Kenkyū-buntansha): 白砂 孔明 東京農業大学, 農学部, 助教 (20552780) ; 臼井 文武 自治医科大学, 医学部, 助教 (50585560) ; 渡邊 幸子 自治医科大学, 医学部, 助教 (80770619)
• Co-Investigator(Renkei-kenkyūsha): TAKAHASHI Masafumi 自治医科大学, 医学部, 教授 (40296108)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: immunoproteasome / obeisty / LMP7 / macrophages / inflammation / diabetes / 免疫プロテアソーム / 脂肪細胞 / 分化 / マクロファージ / M2 / 炎症 / 脂肪 / 肥満 / 糖尿病

Outline of Final Research Achievements

The pathogenic mechanism of inflammation in obesity is not fully understood. Low-molecular-mass polypeptide-7 (LMP7), a proteolytic subunit of the immunoproteasome, plays a critical role in the immune system, and has been involved in the pathogenesis of several autoimmune diseases. We investigated the role of LMP7 in high fat diet-induced obesity using LMP7-deficient mice. LMP7 deficiency decreased body weight gain and fat accumulation, suppressed macrophage infiltration in the adipose tissue, improved glucose sensitivity. LMP7 deficiency also suppressed adipogenesis, and increased gene expression of M2 macrophage markers in fat tissues. These findings demonstrate that LMP7 in both hematopoietic and non-hematopoietic cells contributes to the pathogenesis of obesity.

Research Products

• [Journal Article] Caspse-1 deficiency promotes high-fat diet-induced adipose tissue inflammation and the development of obesity. (2016)
  • Author(s): Kimura H, Karasawa T, Usui F, Kawashima A, Endo Y, Kobayashi M, Sadatomo A, Nakamura J, Iwasaki Y, T Yada,Tsutsui H, Kasahara T, Takahashi M.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 311 Issue: 5 Pages: 881-890
  • DOI: 10.1152/ajpendo.00174.2016
  • Peer Reviewed
• [Journal Article] NLRP3 reduces macrophage interleukin-10 production and enhances the susceptibility to doxorubicin-induced cardiotoxicity. (2016)
  • Author(s): Kobayashi M, Usui F, Karasawa T, Kawashima A, Kimura H, Mizushina Y, Shirasuna K, Mizukami H, Kasahara T, Hasebe N, Takahashi M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 26489-26489
  • DOI: 10.1038/srep26489
  • Peer Reviewed / Open Access
• [Journal Article] Immunoproteasome LMP7 deficiency improves obesity and metabolic disorders. (2015)
  • Author(s): Kimura H, Usui F, Karasawa T, Kawashima A, Shirasuna K, Inoue Y, Komada T, Kobayashi M, Mizushina Y, Kasahara T, Suzuki K, Iwasaki Y, Yada T, Caturegli P, Takahashi M.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 15883-15883
  • DOI: 10.1038/srep15883
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] NLRP3 deficiency improves angiotensin II-induced hypertension but not fetal growth restriction during pregnancy. (2015)
  • Author(s): Shirasuna K, Karasawa T, Usui F, Kobayashi M, Komada T, Kimura A, Ohkuchi A, Taniguchi S, Takahashi M.
  • Journal Title: Endocrinology Volume: 156 Issue: 11 Pages: 4281-4292
  • DOI: 10.1210/en.2015-1408
  • Peer Reviewed / Open Access
• [Journal Article] Role of NLRP3 inflammasomes for rhabdomyolysis-induced acute kidney injury. (2015)
  • Author(s): Komada T, Usui F, Kawashima A, Kimura H, Karasawa T, Inoue Y, Kobayashi M, Mizushina Y, Kasahara T, Taniguchi S, Muto S, Nagata D, Takahashi M.
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 10901-10901
  • DOI: 10.1038/srep10901
  • Peer Reviewed / Open Access
• [Journal Article] Oligomerized CARD16 Promotes Caspase-1 Assembly and IL-1β Processing (2015)
  • Author(s): Tadayoshi Karasawa, Akira Kawashima, Fumitake Usui, Hiroaki Kimura, Koumei Shirasuna, Yoshiyuki Inoue, Takanori Komada, Motoi Kobayashi, Yoshiko Mizushina, Junji Sagara, Masafumi Takahashi
  • Journal Title: FEBS Open Bio Volume: 5 Issue: 1 Pages: 348-356
  • DOI: 10.1016/j.fob.2015.04.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New insights into the function of the immunoproteasome in immune and non-immune cells. (2015)
  • Author(s): Kimura H, Caturegli P, Takahashi M, Suzuki K.
  • Journal Title: Journal of Immunology Research Volume: 2015 Pages: 541984-541984
  • DOI: 10.1155/2015/541984
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1β (2015)
  • Author(s): Mizushina Y, Shirasuna K, Usui F, Karasawa T, Kawashima A, Kimura H, Kobayashi M, Komada T, Inoue Y, Mato N, Yamasawa H, Latz E, Iwakura Y, Kasahara T, Bando M, Sugiyama Y, Takahashi M
  • Journal Title: J Biol Chem Volume: 290 Issue: 8 Pages: 5065-5077
  • DOI: 10.1074/jbc.m114.603217
  • Peer Reviewed / Open Access
• [Journal Article] Interferon-tau attenuates uptake of nanoparticles and secretion of interleukin-1β in macrophages (2014)
  • Author(s): Hara K, Shirasuna K, Usui F, Karasawa T, Mizushina Y, Kimura H, Kawashima A, Ohkuchi A, Matsuyama S, Kimura K, Takahashi M
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: 1-17
  • DOI: 10.1371/journal.pone.0113974
  • Peer Reviewed / Open Access
• [Journal Article] Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced aortic aneurysm (2014)
  • Author(s): Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Yoshimura K, Aoki H, Tsutsui H, Noda T, Sagara J, Taniguchi S, Takahashi M
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 35 Issue: 1 Pages: 127-136
  • DOI: 10.1161/atvbaha.114.303763
  • Peer Reviewed / Open Access
• [Journal Article] Nanosilica-induced placental inflammation and pregnancy complications: Different roles of the inflammasome components NLRP3 and ASC. (2014)
  • Author(s): Shirasuna K, Usui F, Karasawa T, Kimura H, Kawashima A, Mizukami H, Ohkuchi A, Nishimura S, Sagara J, Noda T, Ozawa K, Taniguchi S, Takahashi M.
  • Journal Title: Nanotoxicology Volume: 11 Pages: 1-14
  • Peer Reviewed
• [Journal Article] NLRP3 Regulates Neutrophil Functions and Contributes to Hepatic Ischemia-Reperfusion Injury Independently of Inflammasomes. (2014)
  • Author(s): Inoue Y, Shirasuna K, Kimura H, Usui F, Kawashima A, Karasawa T, Tago K, Dezaki, Nishimura S, Sagara J, Noda T, IwakuraY, Hiroko Tsutsui H, Taniguchi S, Yanagisawa K, Yada T, Yasuda Y, Takahashi M.
  • Journal Title: J Immunol Volume: 192(9) Issue: 9 Pages: 4342-4351
  • DOI: 10.4049/jimmunol.1302039
  • Peer Reviewed / Open Access
• [Presentation] 高脂肪食による肥満性炎症におけるCaspase-1の役割 (2017)
  • Author(s): 木村博昭、唐澤直義、笠原忠、高橋将文
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2017-03-25
• [Presentation] New insights into the role of the immunoproteasome in inflammatory diseases. (2017)
  • Author(s): Hiroaki Kimura, Tadayoshi Karasawa, Tadasahi Kasahara, Patrizio Caturegli, Masafumi Takahashi.
  • Organizer: 第19回武田振興財団生命科学シンポジウム（慢性炎症：機序と制御）
  • Place of Presentation: 武田薬品研修所（大阪府吹田市）
  • Year and Date: 2017-01-20
• [Presentation] 高脂肪食誘導型肥満における免疫プロテアソーム(LMP7)の役割 (2016)
  • Author(s): 木村博昭 唐澤直義 川島晃 臼井文武 笠原忠 鈴木幸一 高橋将文
  • Organizer: 第3７回日本炎症・再生医学会
  • Place of Presentation: みやこメッセ（京都）
  • Year and Date: 2016-06-16
• [Presentation] 脂肪酸結晶によるNLRP3インフラマソームを介した炎症惹起機構の解析 (2016)
  • Author(s): 唐澤直義、臼井文武、川島晃、木村博昭、高橋将文
  • Organizer: 第3７回日本炎症・再生医学会
  • Place of Presentation: みやこメッセ（京都）
  • Year and Date: 2016-06-16
• [Presentation] 横紋筋融解症による急性腎障害におけるNLRP3インフラマソームの役割 (2016)
  • Author(s): 高橋将文、駒田敬則、臼井文武、唐澤直義、川島晃、木村博昭
  • Organizer: 第3７回日本炎症・再生医学会
  • Place of Presentation: みやこメッセ（京都）
  • Year and Date: 2016-06-16
• [Presentation] 高脂肪食による肥満・メタボリック病態における免疫プロテアソーム欠損の有益な効果 (2016)
  • Author(s): 木村博昭 臼井文武 唐澤直義 川島晃 笠原忠 鈴木幸一 岩崎有作 矢田俊彦 高橋将文
  • Organizer: 高脂肪食による肥満・メタボリック病態における免疫プロテアソーム欠損の有益な効果
  • Place of Presentation: 京都国際会館（京都）
  • Year and Date: 2016-04-21
• [Presentation] 免疫プロテアソーム欠損は高脂肪食による肥満を抑制する (2015)
  • Author(s): 木村博昭、臼井文武、唐澤直義、川島晃、笠原忠、岩崎有作、矢田俊彦、高橋将文
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-02
• [Presentation] 横紋筋融解症による急性腎障害におけるNLRP3インフラマソームの役割 (2015)
  • Author(s): 臼井文武、駒田敬則、唐澤直義、川島晃、木村博昭、武藤重明、長田太助、高橋将文
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京）
  • Year and Date: 2015-07-21
• [Presentation] 脂質代謝異常におけるASCの役割 (2015)
  • Author(s): 唐澤直義、木村博昭、臼井文武、川島晃、高橋将文
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京）
  • Year and Date: 2015-07-21
• [Presentation] カスパーゼ1ホモログ分子CARD16による新規炎症惹起機序の解析 (2014)
  • Author(s): 唐澤直義、川島晃、臼井文武、木村博昭、高橋将文
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] NLRP3はインフラマソーム非依存的に肝虚血再灌流障害を軽減する (2014)
  • Author(s): 高橋将文、井上賢之、白砂孔明、臼井文武、川島晃、木村博昭
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] 大動脈瘤形成におけるNLRP3インフラマソームの役割の解明 (2014)
  • Author(s): 臼井文武、木村博昭、唐澤直義、川島晃、高橋将文
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 沖縄県名護市
  • Year and Date: 2014-07-01 – 2014-07-04
• [Presentation] LMP7欠損マウスの甲状腺異常 (2014)
  • Author(s): 木村博昭、川島晃、鈴木幸一、岩間信太郎、Patrizio Caturegli、高橋将文。
  • Organizer: 第8６回日本内分泌学会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Remarks] 自治医科大学炎症・免疫研究部HP
  • URL: http://www.jichi.ac.jp/inflammation/