脂肪蓄積を制御する膜蛋白同定とその可溶性分泌型のアディポサイトカインとしての意義

• Project Area: Molecular Basis and Disorders of Control of Apetite and Fat Accumulation
• Project/Area Number: 23126516
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Okayama University
• Principal Investigator: 和田 淳 岡山大学, 医歯(薬)学総合研究科, 准教授 (30294408)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2012: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2011: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: アディポサイトカイン / 膜蛋白 / 可溶性分泌型分子 / 肥満 / メタボリックシンドローム / 脂肪細胞分化 / 細胞内シグナル

Outline of Annual Research Achievements

【背景】我々はメタボリック症候群の病態に深く関与する遺伝子群を同定するために、内臓脂肪蓄積を来し２型糖尿病・高血圧・脂質異常症を発症するOtsuka Long-Evans Tokushima Fatty (OLETF) ラットを用いて内臓脂肪特異的な遺伝子群のスクリーニングを施行し新規アディポサイトカインvaspinを同定しその意義について研究している。その過程で膜蛋白質であるACAM (Adipocyte adhesion molecule)とGpnmb/OA (Osteoactivin)を同定した。
【目的】Gpnmbは膜蛋白でその可溶性分泌型が報告されているが肥満での役割は不明である。
【方法】GpnmbのR150X変異を有するDBA/2JマウスからGpnmb欠損(KO)マウスを作成し、さらにaP2プロモーターを用いてTgマウスを作製した。またGpnmbのELISAを用いて血中濃度の検討を行った。
【結果】高脂肪食飼育KOマウス、Tgマウスでは野生型と比較して体重・内臓脂肪重量に有意差はなかったが、Tgマウスで肝への脂肪沈着、線維化が著明に抑制された。またELISAにより血中の可溶性分泌型の存在を示され、野生型マウスでは肥満によって血中濃度が上昇し、Tgマウスではさらに血中濃度が上昇していた。
【結論】Gpnmb過剰発現による脂肪肝改善の分子機構として可溶性分泌型の肝組織への抗炎症効果や抗酸化作用が示唆された。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO). (2013)
  • Author(s): Murakami K
  • Journal Title: Diab Vasc Dis Res Volume: 10(1) Issue: 1 Pages: 93-96
  • DOI: 10.1177/1479164112444640
  • Peer Reviewed
• [Journal Article] Telmisartan attenuates diabetic nephropathy by suppressing ixidative stress in db/db mice. (2013)
  • Author(s): Sato-Horiguchi C
  • Journal Title: Nephron Exp Nephrol Volume: 121(3-4) Issue: 3-4 Pages: 97-108
  • DOI: 10.1159/000343102
  • Peer Reviewed
• [Journal Article] Vaspin inhibits apoptosis of endothelial cells as a ligand for cell-surface GRP78/VDAC complex. (2013)
  • Author(s): Nakatsuka A
  • Journal Title: Cir Res Volume: 112(5) Issue: 5 Pages: 771-780
  • DOI: 10.1161/circresaha.111.300049
  • Peer Reviewed
• [Journal Article] Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. (2013)
  • Author(s): Kurose Y
  • Journal Title: BMC Nephrol Volume: 14 Issue: 1 Pages: 23-23
  • DOI: 10.1186/1471-2369-14-23
  • Peer Reviewed
• [Journal Article] Impact of circulating vaspin levels on metabolic variables in elderly twins. (2012)
  • Author(s): Hida K
  • Journal Title: Diabetologia Volume: 55(2) Issue: 2 Pages: 530-532
  • DOI: 10.1007/s00125-011-2385-0
  • Peer Reviewed
• [Journal Article] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. (2012)
  • Author(s): Kanzaki M
  • Journal Title: Endocrinology Volume: 153(2) Issue: 2 Pages: 612-620
  • DOI: 10.1210/en.2011-1579
  • Peer Reviewed
• [Journal Article] Serum vaspin concentrations are closely related to insulin resistance and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. (2012)
  • Author(s): Teshigawara S
  • Journal Title: J Clin Endocrinol Metab Volume: 97(7) Issue: 7 Pages: E1202-E1207
  • DOI: 10.1210/jc.2011-3297
  • Peer Reviewed
• [Journal Article] Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice (2012)
  • Author(s): Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, Koike K, Tsuzaki R, Matsumoto K, Miyake Y, Shiraha H, Morita M, Makino H, Yamamoto K
  • Journal Title: Hepatology Volume: 56(3) Issue: 3 Pages: 912-921
  • DOI: 10.1002/hep.25782
  • Peer Reviewed
• [Journal Article] The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome : a randomized controlled trial (2012)
  • Author(s): Kanzaki M, Wada J, Kikumoto Y, Akagi S, Nakao K, Sugiyama H, Makino H
  • Journal Title: Int J Nephrol Renovasc Dis Volume: 5 Pages: 91-96
  • DOI: 10.2147/ijnrd.s32191
  • Peer Reviewed
• [Journal Article] Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex (2012)
  • Author(s): Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Horiguchi CS, Ogawa D, Matsuki Y, Hiramatsu R, Yagita H, Kakuta S, Iwakura Y, Makino H
  • Journal Title: Diabetes Volume: 61(11) Issue: 11 Pages: 2823-2832
  • DOI: 10.2337/db12-0232
  • NAID: 120005300245
  • Peer Reviewed
• [Journal Article] Activation of liver x receptor inhibits osteopontin and ameliorates diabetic nephropathy. (2012)
  • Author(s): Tachibana H
  • Journal Title: J Am Soc Nephrol Volume: 23(11) Issue: 11 Pages: 1835-1846
  • DOI: 10.1681/asn.2012010022
  • Peer Reviewed
• [Journal Article] The serum vaspin levels are reduced in Japanese chronic hemodialysis patients. (2012)
  • Author(s): Inoue J
  • Journal Title: BMC Nephrol Volume: 13(1) Issue: 1 Pages: 163-163
  • DOI: 10.1186/1471-2369-13-163
  • Peer Reviewed
• [Journal Article] RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21Cip1 pathway in adipocytes (2012)
  • Author(s): Nakatsuka A, et al
  • Journal Title: J Pathol Volume: 226(5) Issue: 5 Pages: 784-795
  • DOI: 10.1002/path.3001
  • Peer Reviewed
• [Journal Article] Impact of circulating vaspin levels on metabolic in elderly twins (2012)
  • Author(s): Hida K, et al
  • Journal Title: Diabetologia Volume: 55(2) Pages: 530-532
  • Peer Reviewed
• [Journal Article] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes (2012)
  • Author(s): Kanzaki M, et al
  • Journal Title: Endocrinology Volume: 51(6) Pages: 619-623
  • Peer Reviewed
• [Journal Article] Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management : a randomized controlled trial (2011)
  • Author(s): Takatori Y, et al
  • Journal Title: Clin J Am Soc Nephrol Volume: 6(6) Pages: 1337-1344
  • Peer Reviewed
• [Presentation] Identification of transmembrnane proteins expressed in adipocytes under obese-state and the roles of soluble forms in fat accumulation. (2012)
  • Author(s): Wada J
  • Organizer: International Symposium for the Study of Obesity “Translational Science and Epidemiology on Adipomedicine; From Lipodystrophy to Obesity”（
  • Place of Presentation: Shiran Kaikan of Kyoto University, Kyoto
  • Year and Date: 2012-10-13
  • Invited
• [Presentation] PEMT deficiency protects from obesity and insulin resistance, but induces severe steathepatitis. (2012)
  • Author(s): 和田淳
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2012-05-17
  • Invited
• [Presentation] シンポジウムCiliopathies;Ciliaは細胞のconductorコレクトリンとprimary cilia (2011)
  • Author(s): 和田淳
  • Organizer: 第54回日本腎臓病学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-15
• [Book] 糖尿病×CKD診療ガイド (2012)
  • Author(s): 和田淳
  • Total Pages: 197
  • Publisher: 南山堂