Identification of a novel factor involved in lifestyle-related disease amelioration by the transcription factor CREB3L3

• Project/Area Number: 16K09738
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Tsukuba
• Principal Investigator: Iwasaki Hitoshi 筑波大学, 医学医療系, 講師 (20626874)
• Co-Investigator(Kenkyū-buntansha): 中川 嘉 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 生活習慣病 / FGF21 / 食餌誘導性肥満 / 糖尿病 / 肥満 / 糖代謝 / 遺伝子発現

Outline of Final Research Achievements

In mice overexpressing CREB3L3 in the liver, the development of diet-induced obesity due to high-fat high-sucrose diet feeding was apparently suppressed. CREB3L3 increased liver gene expression and blood levels of FGF21 and then increased thermogenesis by beigeing, partially explaining CREB3L3 suppressed obesity. Certainly, mating CREB3L3 Tg mice with FGF21 deficient mice canceled those effects. However, the suppression of inflammation seen in adipose tissue of CREB3L3 Tg mice was not canceled. Glucose responsiveness and insulin responsiveness in CREB3L3 Tg mice were also not dependent on FGF21. We found Kisspeptin as a new target gene for CREB3L3, and it was revealed that the increase in expression is a direct action by CREB3L3 and that it contributes to the improvement of insulin resistance by CREB3L3. In this study, we have clarified one of the molecular mechanisms of the improvement effect of obesity by CREB3L3.

Academic Significance and Societal Importance of the Research Achievements

CREB3L3が肥満、糖尿病の改善に寄与する生活習慣病の新たな治療標的となりえることを示した。また、その分メカニズムの一端としてFGF21, Kisspeptinなどの肝臓から分泌される液性因子であることを示した。CREB3L3自身もメジャーな分子ではなく、これからの研究で活性化機構の解明、活性化化合物の同定が進めば、既存の生活習慣病治療薬とは異なる治療戦略の構築が期待できる。
CREB3L3の本課題でも示したように劇的に生活習慣病を改善するにも関わらず、研究は現在まで盛んとは言えない。それゆえ、我々の研究は学術的にも大きな意義がある。

Research Products

• [Journal Article] Elovl6 Deficiency Improves Glycemic Control in Diabetic db / db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity (2017)
  • Author(s): Zhao Hui、Matsuzaka Takashi、Nakano Yuta、Motomura Kaori、Tang Nie、Yokoo Tomotaka、Okajima Yuka、Han Song-iee、Takeuchi Yoshinori、Aita Yuichi、Iwasaki Hitoshi、Yatoh Shigeru、Suzuki Hiroaki、Sekiya Motohiro、Yahagi Naoya、Nakagawa Yoshimi、Sone Hirohito、Yamada Nobuhiro、Shimano Hitoshi
  • Journal Title: Diabetes Volume: 66 Issue: 7 Pages: 1833-1846
  • DOI: 10.2337/db16-1277
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The selective PPARα modulator K-877 efficiently activates the PPARα pathway and improves lipid metabolism in mice (2017)
  • Author(s): Takei K, Han SI, Murayama Y, Satoh A, Oikawa F, Ohno H, Osaki Y, Matsuzaka T, Sekiya M, Iwasaki H, Yatoh S, Yahagi N, Suzuki H, Yamada N, Nakagawa Y, Shimano H.
  • Journal Title: Journal of Diabetes Investigation Volume: in press Issue: 4 Pages: 446-452
  • DOI: 10.1111/jdi.12621
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科
  • URL: https://www.u-tsukuba-endocrinology.jp/
• [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/