脳由来神経栄養因子による摂食脂肪蓄積制御機構の解明

• Project Area: Molecular Basis and Disorders of Control of Apetite and Fat Accumulation
• Project/Area Number: 25126706
• 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: Niigata University
• Principal Investigator: 南野 徹 新潟大学, 医歯学系, 教授 (90328063)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Discontinued (Fiscal Year 2014)
• Budget Amount: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2014: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: BDNF

Outline of Annual Research Achievements

Brain-Derived Neurotrophic Factor（BDNF）は、主に脳内で産生分泌される神経栄養因子であるが、脳内での産生が低下するとうつ病や神経性食思不振症の原因となることが示唆されている。摂食中枢においては、メラノコルチン受容体の下流シグナルとして、TrkB受容体に作用することによって、摂食をネガティブに制御し、末梢の異化反応を促進すると報告されている。しかしながら、BDNFが中枢や末梢組織においてどのような役割を果たしているかについては、まだまだ不明な点が多い。我々は最近、脂肪組織などの末梢組織においてBDNF/TrkBが発現しており、栄養状態によってその発現が変化すること、末梢組織特異的BDNF/TrkB欠失が摂食や脂肪蓄積に影響を与えることなどを観察している。以上より、中枢・末梢組織におけるBDNF/TrkB axisは、何らかの機序によって栄養状態を感知し、相互に作用することによって、摂食や代謝・脂肪蓄積制御に関与している可能性がある。本研究提案では、様々な遺伝子改変マウスを用いて、特に末梢のBDNF/TrkB axisが、どのように摂食や代謝・脂肪蓄積制御に関与しているかを明らかにし、今後の治療標的となりうるかについて検証することを目的とした。
昨年度までの研究成果において、中枢性BDNF欠失マウスでは、過食・肥満・過活動の形質を認めた。aP2-Creを用いた脂肪特異的BDNF/TrkB欠失マウスも同様の形質を認め、その特異性に疑問が残った。そこで、Adipoq-Creを用いて再検証を行ったところ、脂肪細胞特異的BDNF/TrkB欠失マウスでは、摂食や脂肪蓄積には変化を認めなかった。以上より、正常食下における摂食・脂肪蓄積に対しては、脂肪細胞のBDNF/TrkBの役割は低いものと考えられた。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Inhibition of endothelial p53 improves metabolic abnormalities related to dietary obesity. (2014)
  • Author(s): Yokoyama M, Okada S, Nakagomi A, Moriya J, Shimizu I, Nojima A, Yoshida Y, Ichimiya H, Kamimura N, Kobayashi Y, Ohta S, Fruttiger M, Lozano G, Minamino T.
  • Journal Title: Cell Rep Volume: 7 Issue: 5 Pages: 1691-1703
  • DOI: 10.1016/j.celrep.2014.04.046
  • Peer Reviewed / Open Access
• [Journal Article] Emerging issues in radiogenic cataracts and cardiovascular disease. (2014)
  • Author(s): Hamada N, Fujimichi Y, Iwasaki T, Fujii N, Furuhashi M, Kubo E, Minamino T, Nomura T, Sato H.
  • Journal Title: J Radiat Res Volume: 55 Issue: 5 Pages: 831-846
  • DOI: 10.1093/jrr/rru036
  • Peer Reviewed / Open Access
• [Journal Article] Notch signaling regulates the lifespan of vascular endothelial cells via a p16-dependent pathway. (2014)
  • Author(s): Yoshida Y, Hayashi Y, Suda M, Tateno K, Okada S, Moriya J, Yokoyama M, Nojima A, Yamashita M, Kobayashi Y, Shimizu I, Minamino T.
  • Journal Title: PLoS One Volume: 20 Issue: 6 Pages: e100359-e100359
  • DOI: 10.1371/journal.pone.0100359
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. (2014)
  • Author(s): Kitada K, Nakano D, Ohsaki H, Hitomi H, Minamino T, Yatabe J, Felder RA, Mori H, Masaki T, Kobori H, Nishiyama A.
  • Journal Title: J Diabetes Complications Volume: 28 Issue: 5 Pages: 604-611
  • DOI: 10.1016/j.jdiacomp.2014.05.010
  • Peer Reviewed / Open Access
• [Journal Article] A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis. (2014)
  • Author(s): Ito TK, Yokoyama M, Yoshida Y, Nojima A, Kassai H, Oishi K, Okada S, Kinoshita D, Kobayashi Y, Fruttiger M, Aiba A, Minamino T.
  • Journal Title: PLoS One Volume: 9 Issue: 7 Pages: e102186-e102186
  • DOI: 10.1371/journal.pone.0102186
  • Peer Reviewed / Open Access
• [Journal Article] Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of Diabetic Cardiomyopathy. (2014)
  • Author(s): Suzuki H, Kayama Y, Sakamoto M, Iuchi H, Shimizu I, Yoshino T, Katoh D, Nagoshi T, Tojo K, Minamino T, Yoshimura M, Utsunomiya K.
  • Journal Title: Diabetes Volume: 3
  • Peer Reviewed
• [Journal Article] Relative refractoriness of left ventricular contraction underlies human tachycardia-induced mechanical and electrical alternans. (2014)
  • Author(s): Kashimura T, Kodama M, Watanabe T, Tanaka K, Hayashi Y, Ohno Y, Obata H, Ito M, Hirono S, Hanawa H, Minamino T.
  • Journal Title: Pacing Clin Electrophysiol Volume: 37 Issue: 2 Pages: 197-206
  • DOI: 10.1111/pace.12230
  • Peer Reviewed / Open Access
• [Journal Article] Augmentation of the J wave by rapid pacing in a patient with vasospastic angina. (2014)
  • Author(s): Sato A, Watanabe H, Sonoda K, Chinushi M, Tsuda T, Izumi D, Furushima H, Minamino T.
  • Journal Title: Int J Cardiol. Volume: 172 Issue: 1 Pages: e111-e113
  • DOI: 10.1016/j.ijcard.2013.12.121
  • Peer Reviewed / Open Access
• [Journal Article] Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency. (2014)
  • Author(s): Suzuki T, Hanawa H, Jiao S, Ohno Y, Hayashi Y, Yoshida K, Kashimura T, Obata H, Minamino T.
  • Journal Title: J Card Fail Volume: 20 Issue: 4 Pages: 268-277
  • DOI: 10.1016/j.cardfail.2014.01.008
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of bepridil to prevent ventricular fibrillation in severe form of early repolarization syndrome (2014)
  • Author(s): Katsuumi G, Shimizu W, Watanabe H, Noda T, Nogami A, Ohkubo K, Makiyama T, Takehara N, Kawamura Y, Hosaka Y, Sato M, Fukae S, Chinushi M, Oda H, Okabe M, Kimura A, Maemura K, Watanabe I, Kamakura S, Horie M, Aizawa Y, Makita N, Minamino T
  • Journal Title: Int J Cardiol Volume: 172 Issue: 2 Pages: 519-522
  • DOI: 10.1016/j.ijcard.2014.01.036
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of TERT in heterochromatin maintenance. (2014)
  • Author(s): Maida Y, Yasukawa M, Okamoto N, Ohka S, Kinoshita K, Totoki Y, Ito TK, Minamino T, Nakamura H, Yamaguchi S, Shibata T, Masutomi K.
  • Journal Title: Mol Cell Biol Volume: 印刷中 Issue: 9 Pages: 1576-1593
  • DOI: 10.1128/mcb.00093-14
  • Peer Reviewed / Open Access
• [Journal Article] Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia. (2013)
  • Author(s): Watanabe H, van der Werf C, Horie M. et al.
  • Journal Title: Heart Rhythm Volume: 10 Issue: 4 Pages: 542-547
  • DOI: 10.1016/j.hrthm.2012.12.035
  • Peer Reviewed
• [Journal Article] Tumor suppressor p53 inhibits systemic autoimmune diseases by inducing regulatory T cells. (2013)
  • Author(s): Kawashima H, Takatori H, Suzuki K, Iwata A, Yokota M, Suto A, Minamino T, Hirose K, Nakajima H
  • Journal Title: J Immunol. Volume: 19 Issue: 7 Pages: 3614-3623
  • DOI: 10.4049/jimmunol.1300509
  • Peer Reviewed
• [Journal Article] Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells (2013)
  • Author(s): Ozasa Y, Akazawa H, Qin Y, Tateno K, Ito K, Kudo-Sakamoto Y, Yano M, Yabumoto C, Naito AT, Oka T, Lee JK, Minamino T, Nagai T, Kobayashi Y, Komuro I
  • Journal Title: Hypertens Res Volume: 36(10) Issue: 10 Pages: 859-65
  • DOI: 10.1038/hr.2013.52
  • Peer Reviewed
• [Journal Article] Semaphorin-induced inflammation contributes to insulin resistance in dietary obesity. (2013)
  • Author(s): Shimizu I, Yoshida Y, Moriya J, Nojima A, Uemura A, Kobayashi Y, Minamino T.
  • Journal Title: Cell Metab Volume: 18 Issue: 4 Pages: 491-504
  • DOI: 10.1016/j.cmet.2013.09.001
  • Peer Reviewed
• [Journal Article] Malfunction of cardiac resynchronization therapy due to subsequent fracture of the ring and tip conductors of a co-radial left ventricular bipolar lead. (2013)
  • Author(s): Sato A, Chinushi M, Izumi D, Furushima H, Minamino T.
  • Journal Title: Intern Med Volume: 52 Pages: 1189-93
  • NAID: 130003365633
  • Peer Reviewed
• [Journal Article] SCN5A mutation associated with ventricular fibrillation, early repolarization, and concealed myocardial abnormalities (2013)
  • Author(s): Watanabe H, Ohkubo K, Watanabe I, Matsuyama TA, Ishibashi-Ueda H, Yagihara N, Shimizu W, Horie M, Minamino T, Makita N
  • Journal Title: Int J Cardiol. Volume: 165 Issue: 2 Pages: e21-e23
  • DOI: 10.1016/j.ijcard.2012.10.074
  • Peer Reviewed
• [Journal Article] A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene. (2013)
  • Author(s): Watanabe T, Hanawa H, Suzuki T, Jiao S, Yoshida K, Ogura M, Ohno Y, Hayashi Y, Ito M, Kashimura T, Obata H, Sato A, Ozawa T, Kodama M, Sakuraba H, Minamino T.
  • Journal Title: Intern Med. Volume: 52 Pages: 777-80
  • NAID: 130003365972
  • Peer Reviewed
• [Journal Article] Role of mutations in L-type calcium channel genes in Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation associated with right bundle branch block. (2013)
  • Author(s): Watanabe H, Minamino T.
  • Journal Title: Circ J Volume: 77 Pages: 1689-90
  • NAID: 10031173746
  • Peer Reviewed
• [Journal Article] Haploinsufficiency of akt1 prolongs the lifespan of mice (2013)
  • Author(s): Nojima A, Yamashita M, Yoshida Y, Shimizu I, Ichimiya H, Kamimura N, Kobayashi Y, Ohta S, Ishii N, Minamino T
  • Journal Title: PLoS One Volume: 8(7) Issue: 7 Pages: e69178-e69178
  • DOI: 10.1371/journal.pone.0069178
  • Peer Reviewed
• [Journal Article] Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. (2013)
  • Author(s): Bezzina CR, Makita N(63人中31番目)et al
  • Journal Title: Nat Genet. Volume: 45 Issue: 9 Pages: 1044-1049
  • DOI: 10.1038/ng.2712
  • Peer Reviewed / Open Access
• [Presentation] 細胞老化シグナルによる炎症制御と疾患 (2014)
  • Author(s): Minamino T.
  • Organizer: 第135回日本炎症・再生医学会
  • Place of Presentation: 沖縄（万国津梁館）
  • Year and Date: 2014-07-03 – 2014-07-04
  • Invited
• [Presentation] 老化再生からみた循環器疾患治療 (2014)
  • Author(s): Minamino T.
  • Organizer: 第３２回日本臨床科学会甲信越支部総会
  • Place of Presentation: 上越（鵜の浜ニューホテル）
  • Year and Date: 2014-06-29
  • Invited
• [Presentation] 健康寿命の延長は可能か？ (2014)
  • Author(s): Minamino T.
  • Organizer: 日本抗加齢医学会・日本疫学合同シンポジウム
  • Place of Presentation: 大阪（大阪国際会議場）
  • Year and Date: 2014-06-08
  • Invited
• [Presentation] The Efficacy of Combination Therapy in Patients with Pulmonary Hypertension. (2014)
  • Author(s): Minamino T.
  • Organizer: 13th International Pulmonary Hypertension Forum
  • Place of Presentation: Lisbon(ポルトガル）
  • Year and Date: 2014-04-04 – 2014-04-06
  • Invited
• [Presentation] 臓器連関とインスリン感受性 (2013)
  • Author(s): Minamino T.
  • Organizer: 第86回日本内分泌学会総会シンポジウム
  • Place of Presentation: 仙台(仙台国際センター）
  • Invited
• [Presentation] Lifespan regulatory system as a potential therapeutic target for cardiovascular disease. (2013)
  • Author(s): Minamino T.
  • Organizer: International Association of Gerontology and Geriatrics
  • Place of Presentation: seoul(韓国）
  • Invited
• [Presentation] 血管老化とNO (2013)
  • Author(s): Minamino T.
  • Organizer: 第13回日本抗加齢医学会ランチョンセミナー
  • Place of Presentation: 横浜(パシフィコ横浜）
  • Invited
• [Presentation] Circadian clock and cardiovascular aging. (2013)
  • Author(s): Minamino T.
  • Organizer: IEEE EMBC
  • Place of Presentation: Osaka(大阪国際会議場）
  • Invited
• [Presentation] 心-脂肪連関による心不全発症のメカニズム (2013)
  • Author(s): Minamino T.
  • Organizer: 第17回日本心臓リハビリテーション学会シンポジウム
  • Place of Presentation: 仙台(仙台国際センター）
  • Invited
• [Presentation] Role of cellular aging signals in cardiovascular and metabolic disease. (2013)
  • Author(s): Minamino T.
  • Organizer: BCVS
  • Place of Presentation: Las Vegas(アメリカ）
  • Invited
• [Presentation] 老化シグナルネットワークによる循環代謝制御 (2013)
  • Author(s): Minamino T.
  • Organizer: 第86回日本生化学会大会シンポジウム
  • Place of Presentation: 横浜(パシフィコ横浜）
  • Invited
• [Presentation] 血管老化シグナルネットワークによる循環代謝制御 (2013)
  • Author(s): Minamino T.
  • Organizer: 第21回日本血管生物医学会シンポジウム
  • Place of Presentation: 大阪(千里阪急ホテル）
  • Invited
• [Presentation] Role of senescence-associated inflammation in lifestyle-related disease.
  • Author(s): Minamino T.
  • Organizer: ISHR
  • Place of Presentation: San Diego(アメリカ）
  • Invited
• [Presentation] Role of cellular aging signals in lifestyle-related disease.
  • Author(s): Minamino T.
  • Organizer: Harbin Medical University
  • Place of Presentation: Harbin(中国）
  • Invited
• [Presentation] 次世代の血管新生治療の開発
  • Author(s): Minamino T.
  • Organizer: 第22回日本形成外科学会基礎学術集会
  • Place of Presentation: 新潟(朱鷺メッセ）
  • Invited
• [Presentation] 老化からみた心血管治療としてのスタチンの有用性
  • Author(s): Minamino T.
  • Organizer: 第17回日本心不全学会学術集会
  • Place of Presentation: 大宮（大宮ソニックシティー）
  • Invited
• [Presentation] 心血管系の老化のメカニズム
  • Author(s): Minamino T.
  • Organizer: 日本老年医学会 支部・地方会 第24回九州地方支部
  • Place of Presentation: 九州（産業医科大学）
  • Invited
• [Book] セマフォリンと肥満 (2014)
  • Author(s): 吉田陽子、清水逸平、南野 徹
  • Publisher: 診断と治療社
• [Book] 全身浮腫の成因・病態・診断・治療 (2014)
  • Author(s): 小幡裕明、南野 徹
  • Publisher: 医薬ジャーナル社
• [Book] 心不全とインスリン抵抗性 (2014)
  • Author(s): 清水逸平、吉田陽子、南野 徹
  • Publisher: 中外医学社
• [Book] 加齢に伴う心血管系の変化 (2014)
  • Author(s): 清水逸平、吉田陽子、南野 徹
  • Publisher: 科学評論社
• [Book] インスリン抵抗性と心不全 (2013)
  • Author(s): 清水逸平，南野 徹
  • Publisher: 中外医学社
• [Book] 体内時計の分子機構と老化 時間薬理学による最新の治療戦略 (2013)
  • Author(s): 南野 徹
  • Publisher: 医薬ジャーナル社
• [Book] 慢性炎症と生活習慣病 (2013)
  • Author(s): 岡田将、南野 徹
  • Publisher: 南山堂
• [Book] 再生医療事業の課題解決のための手引書 (2013)
  • Author(s): 小澤拓也、南野 徹
  • Publisher: 株式会社技術情報協会
• [Book] 心不全や肥満における脂肪老化シグナルの意義 (2013)
  • Author(s): 清水逸平、南野 徹
  • Publisher: 診断と治療社