Elucidation of the mechanism of appetite from the Perspective of circadian clock system and Intestinal Microbiota

• Project/Area Number: 19K14018
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 08030:Family and consumer sciences, and culture and living-related
• Research Institution: Waseda University
• Principal Investigator: Haraguchi Atsushi 早稲田大学, 理工学術院, 講師(任期付) (80834671)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腸内細菌叢 / 糞便移植 / 水溶性食物繊維 / マウス / 食欲 / 食欲制御 / 短鎖脂肪酸 / 食欲抑制 / 概日時計 / 生体リズム / 時間生物学 / 腸内フローラ

Outline of Research at the Start

概日時計は種々の生理機能の活性に約24時間周期の概日リズムをもたらすことで、生体の恒常性維持に貢献している。また近年の研究により、腸内細菌叢も生体の恒常性維持に重要であることが分かっている。本研究で着目した食欲は生体の恒常性維持に重要であり、概日時計と腸内細菌叢の両方の調節を受けることが分かっているが、その調節がそれぞれ独立した経路によるものなのか、相互作用することで調節しているのかについては分かっていない。
そこで本研究では、概日時計と腸内細菌叢による複合的な観点から食欲調節に関する新たな作用因子や経路を同定することを目的としている。

Outline of Final Research Achievements

We examined the effects of improvement of the intestinal environment by soluble fiber intake on appetite. We confirmed that a high-fat diet containing resistant maltodextrin (RM-HFD), a soluble dietary fiber, decreased food intake and improved the intestinal environment. Furthermore, when fecal microbiota from the mice feeding with RM-HFD were transplanted into other mice, the transplanted mice showed low HFD intake. Although we observed no effects of RM-HFD on appetite from the viewpoints of circadian clock system, the results suggest that soluble fiber intake may be involved in the suppression of excessive appetite.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の成果は、腸内細菌叢・腸内環境の改善が嗜好性の高い食べ物に対する過剰な食欲(本研究では高脂肪食に対する過剰な食欲)の抑制につながる可能性を示唆する基礎的データであり、今後のヒト栄養を考える上での基礎的情報となり得ると考えている。今後さらなる検証が必要ではあるが、本研究ではヒト応用の部分も踏まえて水溶性食物繊維の含有量を決定していることから、ダイエットが必要な肥満患者などに対して食欲を抑制するための新たなターゲットとなることが期待される。

Research Products

• [Journal Article] Polygalae Radix shortens the circadian period through activation of the CaMKII pathway. (2022)
  • Author(s): Haraguchi A, Saito K, Tahara Y, Shibata S.
  • Journal Title: Pharm Biol. Volume: 60 Issue: 1 Pages: 689-698
  • DOI: 10.1080/13880209.2022.2048863
  • Peer Reviewed / Open Access
• [Journal Article] Wheel-running facilitates phase advances in locomotor and peripheral circadian rhythm in social jet lag model mice. (2022)
  • Author(s): Oneda S, Cao S, Haraguchi A, Sasaki H, Shibata S
  • Journal Title: Front Physiol. Volume: 16 Pages: 821199-821199
  • DOI: 10.3389/fphys.2022.821199
  • Peer Reviewed / Open Access
• [Journal Article] Oak extracts modulate circadian rhythms of clock gene expression in vitro and wheel-running activity in mice. (2022)
  • Author(s): Haraguchi A, Du Y, Shiraishi R, Takahashi Y, Nakamura TJ, Shibata S.
  • Journal Title: Sleep Biol. Rhythms Volume: 20 Pages: 255-266
  • Peer Reviewed / Open Access
• [Journal Article] 4’-demethylnobiletin-rich fermented Citrus reticulata (ponkan) attenuated the disturbance in clock gene expression and locomotor activity rhythms caused by high-fat diet feeding (2021)
  • Author(s): Haraguchi Atsushi、Sato Shuhei、Kusano Shuichi、Ito Kaede、Yamazaki Tomohiro、Ryan Conn、Sekiguchi Masataka、Shibata Shigenobu
  • Journal Title: Biological Rhythm Research Volume: 0 Issue: 10 Pages: 1-14
  • DOI: 10.1080/09291016.2021.1968609
  • Peer Reviewed / Open Access
• [Journal Article] Use of a social jetlag-mimicking mouse model to determine the effects of a two-day delayed light- and/or feeding-shift on central and peripheral clock rhythms plus cognitive functioning. (2021)
  • Author(s): Haraguchi A, Nishimura Y, Fukuzawa M, Kikuchi Y, Tahara Y, Shibata S.
  • Journal Title: Chronobiol Int. Volume: 38 Issue: 3 Pages: 426-442
  • DOI: 10.1080/07420528.2020.1858850
  • Peer Reviewed / Open Access
• [Journal Article] The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy (2020)
  • Author(s): Motohashi Hiroaki、Tahara Yu、Whittaker Daniel S.、Wang Huei-Bin、Yamaji Takahiro、Wakui Hiromichi、Haraguchi Atsushi、Yamazaki Mayu、Miyakawa Hiroki、Hama Koki、Sasaki Hiroyuki、Sakai Tomoko、Hirooka Rina、Takahashi Kengo、Takizawa Miku、Makino Saneyuki、Aoyama Shinya、Colwell Christopher S.、Shibata Shigenobu
  • Journal Title: Kidney International Volume: 97 Issue: 4 Pages: 728-740
  • DOI: 10.1016/j.kint.2019.09.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Crosstalk Among Circadian Rhythm, Obesity and Allergy. (2020)
  • Author(s): Orihara K, Haraguchi A, Shibata S.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 5 Pages: 1884-1884
  • DOI: 10.3390/ijms21051884
  • Peer Reviewed
• [Journal Article] Phase resetting of circadian peripheral clocks using human and rodent diets in mouse models of type 2 diabetes and chronic kidney disease. (2019)
  • Author(s): Yasuda S, Iwami S, Tamura K, Ikeda Y, Kamagata M, Sasaki H, Haraguchi A, Miyamatsu M, Hanashi S, Takato Y, Shibata S.
  • Journal Title: Chronobiol Int. Volume: 36 Issue: 6 Pages: 851-869
  • DOI: 10.1080/07420528.2019.1594245
  • Peer Reviewed
• [Journal Article] Correlation among clock gene expression rhythms, sleep quality, and meal conditions in delayed sleep-wake phase disorder and night eating syndrome. (2019)
  • Author(s): Haraguchi A, Komada Y, Inoue Y, Shibata S.
  • Journal Title: Choronobiology International Volume: 未定 Issue: 6 Pages: 1-14
  • DOI: 10.1080/07420528.2019.1585366
  • Peer Reviewed / Open Access
• [Presentation] 腸内細菌叢改善が高脂肪食誘発性食欲促進に与える影響 (2021)
  • Author(s): 原口 敦嗣, 関口 優崇, 伊東 楓, 柴田 重信
  • Organizer: 第8回日本時間栄養学会学術大会, シンポジウム①「食欲と時計」
• [Presentation] High-fat diet feeding at lunch or dinner lead to increase HFD calorie intake, to increase body weight, and to disrupt recognition function. (2021)
  • Author(s): 原口敦嗣, ライアン弧音, 関口優崇, 尾根田諭, 伊東楓, 曹思遠, 田原優, 柴田重信,
  • Organizer: 第28回日本時間生物学会学術大会
• [Presentation] The effects of Polygalae Radix on clock gene expression rhythm and free-running period (2020)
  • Author(s): 原口敦嗣, 斉藤恵祐, 田原優, 柴田重信
  • Organizer: 第27回日本時間生物学会学術大会