Elucidation of the molecular mechanism of the metabolic syndrome induced by long-term dietary nitrite and nitrate deficiency and development of the new treatment

• Project/Area Number: 15H06519
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Eating habits
• Research Institution: University of the Ryukyus
• Principal Investigator: Kina Mika 琉球大学, 医学部附属病院, 医員 (80578914)
• Research Collaborator: SAKANASHI Mayuko ; KANAME Tadashi ; MATSUZAKI Toshihiro ; NOGUCHI Katsuhiko ; NAKASONE Junko ; TAIRA Yuji ; ARASAKI Akira ; TSUTSUI Masato
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: メタボリックシンドローム / nitrate

Outline of Final Research Achievements

In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. To this end, we prepared a low-nitrite/nitrate diet (LND), in which the contents of L-arginine, fat, carbohydrates, protein and energy were identical with a regular diet(RD).
Three months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance in comparison with the RD. Eighteen months of the LND significantly provoked hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction.
These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Research Products

• [Journal Article] Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. (2017)
  • Author(s): Kina-Tanada M, Sakanashi M, Tanimoto A, Kaname T, Matsuzaki T, Noguchi K, Uchida T, Nakasone J, Kozuka C, Ishida M, Kubota H, Taira Y, Totsuka Y, Kina SI, Sunakawa H, Omura J, Satoh K, Shimokawa H, Yanagihara N, Maeda S, Ohya Y, Matsushita M, Masuzaki H, Arasaki A, Tsutsui M.
  • Journal Title: Diabetologia. Volume: 60 Issue: 6 Pages: 1138-1152
  • DOI: 10.1007/s00125-017-4259-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 低 NO2- / NO3- 食の長期的な摂取はメタボリックシンドロームを惹起する (2017)
  • Author(s): 坂梨まゆ子, 喜名美香, 野口克彦, 松崎俊博, 仲宗根淳子, 平良雄司, 久保田陽秋, 戸塚裕一, 筒井正人
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター （宮城県仙台市）
  • Year and Date: 2017-03-24
• [Presentation] 食事中のnitriteおよびnitrateの不足は代謝症候群、内皮機能不全、および心血管死を惹起する (2017)
  • Author(s): 喜名美香 坂梨まゆ子 谷本昭英 松﨑俊博 野口克彦 仲宗根淳子 下川宏明 喜名振一郎 砂川 元 大屋祐輔 新崎 章 筒井正人
  • Organizer: 第46回日本心脈管作動物質学会
  • Place of Presentation: 琉球大学 （沖縄県中頭郡西原町）
  • Year and Date: 2017-02-10
• [Presentation] Long-Term Dietary Nitrite and Nitrate Deficiency Causes Metabolic Syndrome in Mice. (2016)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Ishida M, Uchida T, Kubota H, Matsuzaki T, Noguchi K, Nakasone J, Shimokawa H, Ohya Y, Arasaki A.
  • Organizer: American Heart Association, Scientific Sessions 2016.
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, Lousiana, USA.
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Long-term dietary nitrite and nitrate deficiency causes metabolic syndrome in mice. (2016)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Ishida M, Ohya Y, Shimokawa H, Arasaki A.
  • Organizer: The 9th Interbnational Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide.
  • Place of Presentation: Sendai International Center, Sendai, Japan
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Pathogenetic Role of the Exogenous NO Production System in Metabolic Syndrome. (2016)
  • Author(s): Tsutsui M, Kina-Tanada M, Sakanashi M, Otsuji Y, Shimokawa H, Arasaki A.
  • Organizer: The 9th Interbnational Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Sendai International Center, Sendai, Japan
  • Year and Date: 2016-05-20
  • Int'l Joint Research / Invited