Identification of new causative genes for lipodystrophy and elucidation of adipocyte differentiation/proliferation mechanism

• Project/Area Number: 26461333
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: KUSAKABE Toru 京都大学, 医学研究科, 客員研究員 (60452356)
• 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 脂肪萎縮症 / エクソーム解析 / 脂肪細胞分化 / 脂肪細胞機能 / iPS細胞 / 全ゲノムシークエンス

Outline of Final Research Achievements

Gene analyses were performed in 6 patients with lipodystrophy (3 patients with generalized lipodystrophy and 3 patients with partial lipodystrophy). In one case of congenital generalized lipodystrophy, a new compound heterozygous mutation was identified in the AGPAT2 gene. In the clinical findings, the phenotype of the lipodystrophic patients due to the AGPAT2 gene mutation was different from that of the lipodystrophic patients due to the BSCL2 gene mutation in terms of the severity of lipoatrophy and its complications. Exosome analyses revealed many polymorphisms of genes involved in lipid metabolism. In the future, additional genetic analyses including relatives and functional analyses using their iPS cells will identify new causative genes for lipodystrophy and the mechanism of adipocyte differentiation/proliferation may become clear.

Research Products

• [Journal Article] 日本人の脂肪萎縮糖尿病の成因 (2017)
  • Author(s): 日下部徹、野口倫生、巖西真規、中尾一和
  • Journal Title: BIO Clinica Volume: 32 Pages: 50-52
• [Journal Article] 脂肪萎縮症 (2016)
  • Author(s): 日下部徹、中尾一和
  • Journal Title: 最新医学 Volume: 71 Pages: 85-92
• [Journal Article] Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations (2016)
  • Author(s): 1.E. Mori, J. Fujikura, M. Noguchi, K. Nakao, M. Matsubara, M. Sone, D. Taura, T. Kusakabe, K. Ebihara, T. Tanaka, K. Hosoda, K. Takahashi, I. Asaka, N. Inagaki, K. Nakao
  • Journal Title: Metablism Volume: 65 Issue: 4 Pages: 543-556
  • DOI: 10.1016/j.metabol.2015.12.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ・Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis. (2015)
  • Author(s): Ebihara C, Ebihara K, Aizawa-Abe M, Mashimo T, Tomita T, Zhao M, Gumbilai VM, Kusakabe T, Yamamoto Y, Aotani D, Yamamoto-Kataoka S, Sakai T, Hosoda K, Serikawa T, Nakao K
  • Journal Title: Hum Mol Genet Volume: 24 Issue: 15 Pages: 4238-4249
  • DOI: 10.1093/hmg/ddv156
  • Peer Reviewed
• [Journal Article] Primary Intestinal Follicular Lymphoma and Premature Atherosclerosis in a Japanese Diabetic Patient with Atypical Familial Partial Lipodystrophy (2014)
  • Author(s): Iwanishi M, Ebihara K, Kusakabe T, Washiyama M, Ito-Kobayashi J, Nakamura F, Togawa T, Ozamoto Y, Hagiwara A, Nakao K
  • Journal Title: Internal Medicine Volume: 53 Issue: 8 Pages: 851-858
  • DOI: 10.2169/internalmedicine.53.1713
  • NAID: 130003392773
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Presentation] レプチン治療中の先天性全身性脂肪萎縮症において栄養療法介入が奏功した一例 (2017)
  • Author(s): 古御門恵子, 日下部徹, 冨田努, 森栄作, 大野洋一, 辻秀美, 幣憲一郎, 長嶋一昭, 稲垣暢也
  • Organizer: 第20回日本病態栄養学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2017-01-13
• [Presentation] セイピンノックアウトラットにおける脂肪萎縮の病態解明 (2016)
  • Author(s): 野口倫生, 日下部徹, 泉諒大, 中尾一和
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウンビル
  • Year and Date: 2016-10-07
• [Presentation] AGPAT2遺伝子変異による脂肪萎縮症～我が国における先天性全身性脂肪萎縮症の遺伝子解析 (2016)
  • Author(s): 日下部徹, 田中智洋, 宮澤崇, 青谷大介, 野口倫生, 阿部恵, 海老原健, 中尾一和
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウンビル
  • Year and Date: 2016-10-07
• [Presentation] BSCL2遺伝子異常を有する先天性全身性脂肪萎縮症患者からの疾患特異的iPS細胞樹立と解析 (2016)
  • Author(s): 森栄作, 藤倉純二, 中尾一泰, 野口倫生, 日下部徹, 海老原健, 田中智之, 浅香勲, 細田公則, 稲垣暢也, 中尾一和
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-05-19
• [Presentation] Investigating the role of betatrophin in glucose and lipid metabolism using betatrophin knockout rats (2015)
  • Author(s): Toru Kusakabe, Ryota Izumi, Michio Noguchi, Hiroshi Iwakura, Hiroyuki Koyama, Mika Bando, Takashi Miyazawa, Kiminori Hosoda, Kenji Kangawa, Kazuwa Nakao
  • Organizer: ・Keystone symposia 2015: Diabetes
  • Place of Presentation: Kyoto
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] Effect of leptin-replacement therapy on acanthosis nigricans in congenital generalized lipodystrophy (2014)
  • Author(s): Toru Kusakabe, Ken Ebihara, Daisuke Aotani, Megumi Aizawa-Abe, Sachiko Kataoka-Yamamoto, Takeru Sakai, Chihiro Ebihara, Junji Fujikura, Kiminori Hosoda, Kazuwa Nakao
  • Organizer: Lipodystrophy in 2014: Leptin and Beyond
  • Place of Presentation: ミシガン大学（アメリカ合衆国）
  • Year and Date: 2014-10-17 – 2014-10-19
• [Presentation] Efficacy of leptin therapy in diabetes: lessons from lipodystrophy (2014)
  • Author(s): Toru Kusakabe
  • Organizer: The Conference on Bioactive Peptides for Cell-Cell Communication 2014
  • Place of Presentation: 京都グランヴィア（京都府・京都市）
  • Year and Date: 2014-09-10 – 2014-09-12
  • Invited