Association of maternal fructose intake and offspring insulin resistance

• Project/Area Number: 17K07805
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Food science
• Research Institution: Fujita Health University
• Principal Investigator: Ohashi Koji 藤田医科大学, 保健学研究科, 教授 (60278281)
• Co-Investigator(Kenkyū-buntansha): 宗綱 栄二 藤田医科大学, 医学部, 助教 (30600431)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: フルクトース / DOHaD / インスリン抵抗性 / エピジェネティクス / 果糖 / 栄養 / メタボリックシンドローム / micro RNA / DNAメチル化 / 分子栄養学

Outline of Final Research Achievements

Fructose is used as a sweetener in many beverages. We have found that pups from fructose-fed dams develop insulin resistances. This study investigates the pathogenic mechanism from the viewpoint of DOHaD (developmental origin of health and illness), and elucidates the molecular mechanism of maternal fructose-induced effects from an epigenetic perspective. As a result, miR regulation of Lxra expression, which is involved in the induction of insulin resistance, and increased DNA methylation rate of stat3 gene promoter were observed. It was suggested that epigenetic effects are involved in the induction of adverse effects on the next generation by fructose intake during pregnancy.

Academic Significance and Societal Importance of the Research Achievements

「健康や疾患の素因は胎児期における栄養状態によって形成される」という新しい概念であるDOHaD（Developmental Origin of Health & Disease）説が提唱され、妊娠期の栄養状態が世代を超え、その子どもの将来にも大きく影響を及ぼすことが示唆されている。日本をはじめとする先進国において、妊婦のフルクトース摂取は増加の一途をたどっている。本研究はフルクトースの過剰摂取が、次世代に及ぼす影響を明らかにするものであり、現代社会におけるフルクトース過剰摂取の悪影響をDOHaD説により証明するものである。これは胎生期における疾患リスクの形成を阻止する予防医学につながる。

Research Products

• [Journal Article] Maternal fructose consumption down-regulates Lxra expression via miR-206-mediated regulation. (2020)
  • Author(s): Yamazaki M, Munetsuna E, Yamada H, Ando Y, Mizuno G, Fujii R, Nouchi Y, Kageyama I, Teshigawara A, Ishikawa H, Suzuki K, Shimono Y, Hashimoto S, Ohashi K.
  • Journal Title: J Nutr Biochem Volume: 14 Pages: 108386-108386
  • DOI: 10.1016/j.jnutbio.2020.108386
  • Peer Reviewed
• [Journal Article] Maternal fructose-induced oxidative stress occurs via Tfam and Ucp5 epigenetic regulation in offspring hippocampi. (2019)
  • Author(s): Yamada H, Munetsuna E, Yamazaki M, Mizuno G, Sadamoto N, Ando Y, Fujii R, Shiogama K, Ishikawa H, Suzuki K, Shimono Y, Ohashi K, Hashimoto S
  • Journal Title: FASEB journao Volume: 33 Issue: 10 Pages: 11431-11442
  • DOI: 10.1096/fj.201901072r
  • Peer Reviewed
• [Journal Article] Maternal high-fructose intake increases circulating corticosterone levels via decreased adrenal corticosterone clearance in adult offspring. (2019)
  • Author(s): Munetsuna E, Yamada H, Yamazaki M, Ando Y, Mizuno G, Hattori Y, Sadamoto N, Ishikawa H, Ohta Y, Fujii R, Suzuki K, Hashimoto S, Ohashi K
  • Journal Title: Journal of nutritional biochemistry Volume: 67 Pages: 44-50
  • DOI: 10.1016/j.jnutbio.2019.01.016
  • Peer Reviewed
• [Journal Article] Maternal fructose intake disturbs ovarian estradiol synthesis in rats (2018)
  • Author(s): Munetsuna E, Yamada H, Yamazaki M, Ando Y, Mizuno G, Ota T, Hattori Y, Sadamoto N, Suzuki K, Ishikawa H, Hashimoto S, Ohashi K.
  • Journal Title: Life Sciences Volume: 印刷中 Pages: 1231-1239
  • DOI: 10.1016/j.lfs.2018.04.006
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Maternal fructose consumption during gestation and lactation downregulated Igf-1 expression in offspring rat (2019)
  • Author(s): Yoshitaka Ando, Hiroya Yamada, Yuji Hattori, Mirai Yamazaki, Eiji Munetsuna, Hiroaki Ishikawa, Genki Mizuno, Yuri Murase, Nao Sadamoto, Daiki Shimodaira, Ryoji Teradaira, Koji Ohashi
  • Organizer: 国際DOHaD学会
  • Int'l Joint Research
• [Presentation] Excess maternal fructose consumption affects estradiol synthesis in rat offspring (2019)
  • Author(s): Eiji Munetsuna, Hiroya Yamada, Mirai Yamazaki, Yoshitaka Ando, Genki Mizuno, Yuji Hattori, Nao Sadamoto, Koji Suzuki, Hiroaki Ishikawa, Shuji Hashimoto, Koji Ohashi
  • Organizer: 国際DOHaD学会
  • Int'l Joint Research
• [Presentation] 母獣のHigh Fructose Corn Syrup過剰摂取が仔の糖・脂質代謝に与える影響 (2019)
  • Author(s): 貞本奈緒、山田宏哉、宗綱栄二、安藤嘉崇、山崎未来、水野元貴、下平大輝、勅使河原篤志、影山斎、野内佑起、石川浩章、大橋鉱二
  • Organizer: 日本DOHaD学会
• [Presentation] 母獣のフルクトース過剰摂取が次世代のエストロゲン合成に及ぼす影響 (2018)
  • Author(s): 宗綱栄二, 山田宏哉, 山崎未来, 水野元貴, 太田駿瑠, 石川浩章, 鈴木康司, 大橋鉱二
  • Organizer: 日本内分泌学会
• [Presentation] 母獣のフルクトース過剰摂取が仔海馬 Uncoupling Proteins 発現に与える影響 (2018)
  • Author(s): 貞本奈緒、水野元貴、山田宏哉、宗綱栄二、山崎未来、服部裕次、下平大輝、安藤嘉崇、石川浩章、鈴木康司、大橋鉱二
  • Organizer: 日本DOHaD研究会
• [Presentation] 母獣のフルクトース過剰摂取が次世代のエストロゲン合成に及ぼす影響 (2018)
  • Author(s): 宗綱 栄二, 山田 宏哉, 山崎 未来, 水野 元貴, 太田 駿瑠, 石川 浩章, 鈴木 康司, 大橋 鉱二
  • Organizer: 第91回日本内分泌学会学術集会
• [Presentation] 母獣のフルクトース過剰摂取が仔海馬の脳由来神経栄養因子の発現に及ぼす影響 (2018)
  • Author(s): 山崎 未来, 山田 宏哉, 宗綱 栄二, 水野 元貴, 鈴木 康司, 石川 浩章, 橋本 修二, 大橋 鉱二
  • Organizer: 第91回日本内分泌学会学術集会
• [Book] Epigenetics and fructose metabolism: A new mechanism of fructose effects (2019)
  • Author(s): Munetsuna, E., Yamazaki, M., Ohashi, K., Yamada, H.
  • Publisher: Elsevier
• [Book] High-fructose consumption and the epigenetics of DNA methylation (2019)
  • Author(s): Yamada, H., Munetsuna, E., Ohashi, K.
  • Publisher: SprikkerLink