Identification of novel mechanisms in obesity development.

• Project/Area Number: 23591293
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: YAMADA Tetsuya 東北大学, 医学(系)研究科(研究院), 准教授 (90400374)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 臓器間相互作用 / 褐色脂肪組織 / 肝臓 / 自律神経 / 迷走神経 / 交感神経 / グルコキナーゼ / 褐色脂肪 / 肥満 / 糖尿病 / エネルギー代謝

Research Abstract

Despite remarkable advancements in obesity research over the past decade, the mechanisms underlying obesity are still not fully understood. In this study, we discovered a new inter-organ neural network from the liver. In states of energy intake beyond physiological requirements, glucose metabolism changes in the liver with the induction of neuronal signal transmissions via the vagal nerve. These signals, received by the brain, result in the inactivation of sympathetic innervation of brown adipose tissue (BAT). This leads to suppression of thermogenesis in BAT and thereby favors obesity development. During periods when sufficient food was not always available, this system worked in favor of survival. However, in the current age of plenty, it is assumed to work as a mechanism flipping a metabolic switch toward obesity. Furthermore, the efficacy of the liver-to-BAT interaction differs among mouse strains and these differences may contribute to determining the obesity predispositions.

Research Products

• [Journal Article] Glycogen shortage during fasting triggers liver-brain-adipose neurocircuitry to facilitate fat utilization. (2013)
  • Author(s): Izumida Y, Yahagi N, Takeuchi Y, Nishi M, Shikama A, Takarada A, Masuda Y, Kubota M, Matsuzaka T, Nakagawa Y, Iizuka Y, Itaka K, Kataoka K, Shioda S, Niijima A, Yamada T, Katagiri H, Nagai R, Yamada N, Kadowaki T, Shimano H
  • Journal Title: Nat Commun. Volume: 4 Issue: 1 Pages: 2316-2316
  • DOI: 10.1038/ncomms3316
  • Peer Reviewed / Open Access
• [Journal Article] Bach1 deficiency protects pancreatic β-cells from oxidative stress injury. (2013)
  • Author(s): Kondo K, Ishigaki Y, Gao J, Yamada T, Imai J, Sawada S, Muto A, Oka Y, Igarashi K, Katagiri H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 305(5) Issue: 5 Pages: E641-E648
  • DOI: 10.1152/ajpendo.00120.2013
  • Peer Reviewed
• [Journal Article] Inter-organ communications mediate crosstalk between glucose and energy metabolism. (Review) (2013)
  • Author(s): Yamada T
  • Journal Title: Diabetol Int Volume: 4(3) Pages: 149-155
  • URL: http://link.springer.com/article/10.1007%2Fs13340-013-0133-z
  • Peer Reviewed
• [Journal Article] Identification of a novel inter-organ mechanism favoring energy storage in over-nutrition (2013)
  • Author(s): Yamada T (corresponding author), Tsukita S, Katagiri H
  • Journal Title: Adipocyte Volume: 2(4) Issue: 4 Pages: 281-284
  • DOI: 10.4161/adip.25499
  • Peer Reviewed
• [Journal Article] Cognitive dysfunction associated with anti-glutamic acid decarboxylase autoimmunity : a case-control study (2013)
  • Author(s): Takagi M, Ishigaki Y, Uno K, Sawada S, Imai J, Kaneko K, Hasegawa Y, Yamada T, Tokita A, Iseki K, Kanno S, Nishio Y, Katagiri H, Mori E
  • Journal Title: BMC Neurol Volume: 13 Issue: 1 Pages: 295-295
  • DOI: 10.1186/1471-2334-13-295
  • Peer Reviewed
• [Journal Article] 臓器間相互作用が司る糖代謝とエネルギー代謝のクロストーク (2013)
  • Author(s): 山田哲也
  • Journal Title: 糖尿病(Journal of the Japan Diabetes Society) Volume: 56(10) Pages: 718-720
  • NAID: 130004905352
  • URL: https://www.jstage.jst.go.jp/article/tonyobyo/56/10/56_718/_pdf
  • Peer Reviewed
• [Journal Article] Cognitive dysfunction associated with anti-glutamic acid decarboxylase autoimmunity: a case-control study. (2013)
  • Author(s): Takagi M, Ishigaki Y, Uno K, Sawada S, Imai J, Kaneko K, Hasegawa Y, Yamada T, Tokita A, Iseki K, Kanno S, Nishio Y, Katagiri H and Mori E
  • Journal Title: BMC Neurol Volume: 13 Issue: 1 Pages: 76-76
  • DOI: 10.1186/1471-2377-13-76
  • Peer Reviewed
• [Journal Article] Chronic mild stress alters circadian expressions of molecular clock genes in the liver. (2013)
  • Author(s): Takahashi K, Yamada T (corresponding author), Tsukita S, Kaneko K, Shirai Y, Munakata Y, Ishigaki Y, Imai J, Uno K, Hasegawa Y, Sawada S, Oka Y, Katagiri H.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 304(3)
  • Peer Reviewed
• [Journal Article] Chronic mild stress alters circadian expressions ofmolecular clock genes in the liver (2012)
  • Author(s): Takahashi K, Yamada T, Tsukita S, Kaneko K, Shirai Y, Munakata Y, Ishigaki Y, Imai J, Uno K, Hasegawa Y, Sawada S, Oka Y, Katagiri H.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 304(3) Issue: 3 Pages: E301-E309
  • DOI: 10.1152/ajpendo.00388.2012
  • Peer Reviewed
• [Journal Article] Importance of endothelial NF-κB signaling in vascular remodeling and aortic aneurysm formation (2012)
  • Author(s): Saito T, Hasegawa Y, Ishigaki Y, Yamada T, Gao J, Imai J, Uno K, Kaneko K, Ogihara T, Shimosawa T, Asano T, Fujita T, Oka Y, Katagiri H.
  • Journal Title: Cardiovascular Research Volume: 97(1) Issue: 1 Pages: 106-114
  • DOI: 10.1093/cvr/cvs298
  • Peer Reviewed
• [Journal Article] Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals (2012)
  • Author(s): Tsukita S, Yamada T, Uno K, Takahashi1 K, Kaneko K, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Ishihara H, Oka Y, Katagiri H
  • Journal Title: Cell Metab Volume: 16(6) Pages: 825-32
  • Peer Reviewed
• [Journal Article] A case of slowly progressive type 1 diabetes with insulin independence maintained for 10 years withα-glucosidase inhibitor monotherapy (2012)
  • Author(s): Munakata Y, Yamada T (corresponding author), Takahashi K, Tsukita S, Takahashi K, Sawada S, Imai J, Ishigaki Y, Oka Y, Katagiri H
  • Journal Title: Intern Med Volume: 51(24) Pages: 3391-4
  • NAID: 130003308166
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/23257526
  • Peer Reviewed
• [Journal Article] Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans (2012)
  • Author(s): Hasegawa Y, Fujita T, et al.
  • Journal Title: Circulation Volume: 125 Issue: 9 Pages: 1122-1133
  • DOI: 10.1161/circulationaha.111.054346
  • Peer Reviewed
• [Journal Article] Hepatic peroxisome proliferator-activated receptor-{gamma}-fat-specific protein 27 pathway contributes to obesity-related hypertension via afferent vasal signals (2012)
  • Author(s): Uno K, Yamada T, Ishigaki Y, Imai J, Hasegawa Y, Gao J, Kaneko K, Matsusue K, Yamazaki T, Oka Y, Katagiri H
  • Journal Title: Eur Heart J Volume: (In Press) Issue: 10 Pages: 1279-1289
  • DOI: 10.1093/eurheartj/ehr265
  • Peer Reviewed
• [Journal Article] エネルギー代謝の中枢神経支配 (2012)
  • Author(s): 山田哲也
  • Journal Title: 糖尿病(Journal of the Japan Diabetes Society) Volume: 55(5) Pages: 309-312
  • NAID: 10030976789
  • URL: http://search.jamas.or.jp/index.php
  • Peer Reviewed
• [Journal Article] Hepatic glucokinase modulates obesity predisposition by regulating BAT thermogenesis via neural signals (2012)
  • Author(s): Tsukita S, Yamada T, Uno K, Takahashi K, Kaneko K, Ishigaki Y, Imai J, Hasegawa Y, Sawada S, Ishihara H, Oka Y, Katagiri H.
  • Journal Title: Cell Metab Volume: 16(6) Issue: 6 Pages: 825-832
  • DOI: 10.1016/j.cmet.2012.11.006
  • Peer Reviewed
• [Journal Article] NF-kappaB 経路と老化についての論文 (2012)
  • Author(s): Hasegawa Y, Saito T, Ogihara T, Yamada T et al
  • Journal Title: Circulation Volume: 125 Pages: 1122-1133
  • Peer Reviewed
• [Journal Article] CHOPの動脈硬化における役割についての論文 (2012)
  • Author(s): Gao J, Ishigaki Y, Yamada T, Imai J et al.
  • Journal Title: Circulation Volume: 124 Pages: 830-839
  • Peer Reviewed
• [Journal Article] Cognitive decline in a patient with anti-glutamic acid decarboxylase autoimmunity; case report (2011)
  • Author(s): Takagi M, Yamasaki H, Endo K, Yamada T, Kaneko K, Oka Y, Mori E
  • Journal Title: BMC Neurol Volume: 11 Issue: 1 Pages: 156-156
  • DOI: 10.1186/1471-2377-11-156
  • Peer Reviewed
• [Journal Article] Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses (2011)
  • Author(s): Gao J, Ishigaki Y, Yamada T, Kondo K, Yamaguchi S, Imai J, Uno K, HasegawaY, Sawada S, Ishihara H, Oyadomari S, Mori M, Oka Y, Katagiri H
  • Journal Title: Circulation Volume: 124 Issue: 7 Pages: 830-839
  • DOI: 10.1161/circulationaha.110.014050
  • Peer Reviewed
• [Journal Article] Frequent loss of genome gap region in 4p16.3 subtelomere in early-onset type 2 diabetes mellitus (2011)
  • Author(s): Kudo H, Emi M, Ishigaki Y, Tsunoda U, Hinokio Y, Ishii M, Sato H, Yamada T, Katagiri H, Oka Y
  • Journal Title: Exp Diabetes Res Volume: 2011 Pages: 498460-498460
  • DOI: 10.1155/2011/498460
  • Peer Reviewed
• [Journal Article] Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle (2011)
  • Author(s): Sugita S, Kamei Y, Akaike F, Suganami T, Kanai S, Hattori M, Manabe Y, Fujii N, Takai-Igarashi T, Tadaishi M, Oka J, Aburatani H, Yamada T, Katagiri H, Kakehi S, Tamura Y, Kubo H, Nishida K, Miura S, Ezaki O, Ogawa Y
  • Journal Title: PLoS One Volume: 6(5) Issue: 5 Pages: e20467-e20467
  • DOI: 10.1371/journal.pone.0020467
  • Peer Reviewed
• [Journal Article] Interleuki n-6 enhances glucose-stimulated insu lin secretion from pancreatic beta-cells : potential involvement of the PLC-IP3 dependent pathway. (2011)
  • Author(s): Suzuki T, Imai J, Yamada T, IshigakiY, Kaneko K, Uno K, Hasegawa Y, Ishihara H, Oka Y, Katagiri H
  • Journal Title: Diabetes Volume: 60 Issue: 2 Pages: 537-547
  • DOI: 10.2337/db10-0796
  • Peer Reviewed
• [Presentation] 臓器間ネットワークからみた肥満・2型糖尿病(シンポジウム6:臓器からみた糖尿病の病態と治療) (2014)
  • Author(s): 山田哲也、片桐秀樹
  • Organizer: 第48回糖尿病学の進歩
  • Place of Presentation: 札幌市
  • Year and Date: 2014-03-08
• [Presentation] Inter-organ neural network mediate body weight regulation (2014)
  • Author(s): Tetsuya Yamada, Sohei Tsukita, Hideki Katagiri
  • Organizer: The 91st Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Kagoshima
• [Presentation] 臓器間ネットワークからみた肥満・２型糖尿病 (2014)
  • Author(s): 山田 哲也、片桐 秀樹
  • Organizer: 第４８回糖尿病学の進歩
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Inter-organ neural network media te body weight regulation. (2014)
  • Author(s): Tetsuya Yamada, Sohei Tsukita, Hideki Katagiri
  • Organizer: The 91st Annual Meeting of the Physiological Society of Japan.
  • Place of Presentation: Kagoshima
  • Invited
• [Presentation] 臓器間神経ネットワークによる体重調節機構の解明(日本肥満学会学術奨励賞受賞講演) (2013)
  • Author(s): 山田哲也
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京
  • Year and Date: 2013-10-12
• [Presentation] 肝からの臓器間ネットワークによるエネルギー代謝制御 (2013)
  • Author(s): 山田哲也、突田壮平、岡芳知、片桐秀樹
  • Organizer: 第56回日本糖尿病学会年次学術集会シンポジウム10:糖代謝と肝臓
  • Place of Presentation: 熊本市
  • Year and Date: 2013-05-17
• [Presentation] 臓器間相互作用が司る糖代謝とエネルギー代謝のクロストーク (2013)
  • Author(s): 山田哲也
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市(日本糖尿学会学会賞(リリー賞)受賞講演)
  • Year and Date: 2013-05-16
• [Presentation] 臓器間相互作用が司る糖代謝とエネルギー代謝のクロストーク (2013)
  • Author(s): 山田 哲也
  • Organizer: 第５６回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 肝からの臓器間ネットワークによるエネルギー代謝制御 (2013)
  • Author(s): 山田 哲也
  • Organizer: 第５６回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 臓器間神経ネットワークによる体重調節機構の解明 (2013)
  • Author(s): 山田 哲也
  • Organizer: 第３４回日本肥満学会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 神経系を介した臓器間相互作用による体重調整 (2012)
  • Author(s): 山田哲也、岡芳知、片桐秀樹
  • Organizer: 第16回日本心血管内分泌代謝学会学術総会(シンポジウム1:臓器間ネットワークによる心血管内分泌代謝調節)
  • Place of Presentation: 東京
  • Year and Date: 2012-11-24
• [Presentation] 神経系を介した臓器間相互作用による体重調節機構 (2012)
  • Author(s): 山田哲也、片桐秀樹、岡芳知
  • Organizer: 第85回日本内分泌学会学術総会シンポジウム14:中枢と末梢の機能調節連関
  • Place of Presentation: 名古屋市
  • Year and Date: 2012-04-21
• [Presentation] 神経系を介した臓器間相互作用による体重調整 (2012)
  • Author(s): 山田哲也、岡芳知、片桐秀樹
  • Organizer: 第１６回 日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 神経系を介した臓器間相互作用による体重調節機構 (2012)
  • Author(s): 山田哲也、片桐秀樹、岡 芳知
  • Organizer: 第８５回 日本内分泌学会学術総会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 褐色脂肪組織における熱産生抑制につながる組織間ネットワーク
  • Author(s): 突田壮平、山田哲也 et al
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌