The mechanism of high fat diet induced neural inflammation and obese

• Project/Area Number: 16K09761
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: University of Miyazaki
• Principal Investigator: Sakoda Hideyuki 宮崎大学, 医学部, 講師 (50376464)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: グレリン / 肥満 / 摂食中枢 / 自律神経 / 炎症 / 糖尿病 / 糖脂質代謝 / ペプチド / エネルギー・糖質代謝異常

Outline of Final Research Achievements

In mice, ghrelin’s orexigenic activity was abolished after 2-4 weeks HFD, consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie-restricted weight loss restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines.
Aged mice easily gained weight during short-term HFD feeding, and required many days to adapt their energy intake. One-day HFD in aged mice induced inflammation in the distal colon, but not in the nodose ganglion or hypothalamus. The anorexic effect of GLP-1 was attenuated in aged mice. mRNA expression of the gene encoding the GLP-1 receptor in the nodose ganglion was significantly lower in aged mice than in young mice. These findings suggest that adaptation of energy intake regulation was attenuated in aged mice, causing them to become obese in response to short-term HFD feeding.

Academic Significance and Societal Importance of the Research Achievements

過栄養や糖代謝異常による慢性炎症が、迷走神経節や視床下部にも及び、ペプチド受容体の発現低下から摂食行動の異常に至る分子機序を明らかにした。加齢によって自律神経を介する摂食調節機構が減弱し高脂肪食による肥満を生じやすくなる可能性が示唆された。

Research Products

• [Journal Article] Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation (2019)
  • Author(s): Ueda Koji、Nakatsu Yusuke、Yamamotoya Takeshi、Ono Hiraku、Inoue Yuki、Inoue Masa-Ki、Mizuno Yu、Matsunaga Yasuka、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Takahashi Shin-Ichiro、Matsubara Akio、Asano Tomoichiro
  • Journal Title: Oncotarget Volume: 10 Issue: 17 Pages: 1637-1648
  • DOI: 10.18632/oncotarget.26691
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep. Volume: 26 Issue: 12 Pages: 3221-3230
  • DOI: 10.1016/j.celrep.2019.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impaired adaptation of energy intake induces severe obesity in aged mice on a high-fat diet (2019)
  • Author(s): Okada Tadashi、Mita Yuichiro、Sakoda Hideyuki、Nakazato Masamitsu
  • Journal Title: Physiological Reports Volume: 7 Issue: 3 Pages: e13989-e13989
  • DOI: 10.14814/phy2.13989
  • Peer Reviewed / Open Access
• [Journal Article] The Xanthine Oxidase Inhibitor Febuxostat Suppresses the Progression of IgA Nephropathy, Possibly via Its Anti-Inflammatory and Anti-Fibrotic Effects in the gddY Mouse Model (2018)
  • Author(s): Inoue Masa-Ki、Yamamotoya Takeshi、Nakatsu Yusuke、Ueda Koji、Inoue Yuki、Matsunaga Yasuka、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Suzuki Yusuke、Asano Tomoichiro、Kushiyama Akifumi
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 12 Pages: 3967-3967
  • DOI: 10.3390/ijms19123967
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of Gut-Derived Secretory Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Their Possible Clinical Applications (2018)
  • Author(s): Okubo Hirofumi、Kushiyama Akifumi、Nakatsu Yusuke、Yamamotoya Takeshi、Matsunaga Yasuka、Fujishiro Midori、Sakoda Hideyuki、Ohno Haruya、Yoneda Masayasu、Asano Tomoichiro
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 10 Pages: 3064-3064
  • DOI: 10.3390/ijms19103064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective Effect of Sex Hormone-Binding Globulin against Metabolic Syndrome: In Vitro Evidence Showing Anti-Inflammatory and Lipolytic Effects on Adipocytes and Macrophages (2018)
  • Author(s): Yamazaki Hiroki、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Yamamotoya Takeshi、Nakatsu Yusuke、Kikuchi Takako、Kaneko Sunao、Tanaka Hirotoshi、Asano Tomoichiro
  • Journal Title: Mediators of Inflammation Volume: 2018 Pages: 1-12
  • DOI: 10.1155/2018/3062319
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of peripheral ghrelin signaling via the vagus nerve in ghrelin receptor?restored GHSR-null mice (2018)
  • Author(s): Okada Tadashi、Waise T.M. Zaved、Toshinai Koji、Mita Yuichiro、Sakoda Hideyuki、Nakazato Masamitsu
  • Journal Title: Neuroscience Letters Volume: 681 Pages: 50-55
  • DOI: 10.1016/j.neulet.2018.05.035
  • Peer Reviewed / Open Access
• [Journal Article] Restoration of metabolic inflammation-related ghrelin resistance by weight loss. (2018)
  • Author(s): Naznin F, Toshinai K, Waise TZ, Okada T, Sakoda H, Nakazato M.
  • Journal Title: J Mol Endocrinol. Volume: 60 Issue: 2 Pages: 109-118
  • DOI: 10.1530/jme-17-0192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity. (2017)
  • Author(s): Yamamotoya T, Nakatsu Y, Kushiyama A, Matsunaga Y, Ueda K, Inoue Y, Inoue MK, Sakoda H, Fujishiro M, Ono H, Kiyonari H, Ishihara H, Asano T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-017-13432-x
  • Peer Reviewed / Open Access
• [Journal Article] Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic β cells. (2017)
  • Author(s): Zhang W, Sakoda H, Miura A, Shimizu K, Mori K, Miyazato M, Takayama K, Hayashi Y, Nakazato M.: Neuromedin U
  • Journal Title: Biochem Biophys Res Commun, Volume: 493 Issue: 1 Pages: 677-683
  • DOI: 10.1016/j.bbrc.2017.08.132
  • Peer Reviewed / Open Access
• [Journal Article] NERP-2 regulates gastric acid secretion and gastric emptying via the orexin pathway. (2017)
  • Author(s): Cherl Namkoong, Koji Toshinai, Zaved Waise, Hideyuki Sakoda, Kazuki Sasaki, Yoichi Ueta, Min-Seon Kim, Naoto Minamino, Masamitsu Nakazato.
  • Journal Title: Biochem Biophys Res Commun Volume: 485 Issue: 2 Pages: 409-413
  • DOI: 10.1016/j.bbrc.2017.02.064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reduced SHARPIN and LUBAC formation may contribute to CCl₄ - Or acetaminophen-induced liver cirrhosis in mice (2017)
  • Author(s): Yamamotoya T, Nakatsu Y, Matsunaga Y, Fukushima T, Yamazaki H, Kaneko S, Fujishiro M, Kikuchi T, Kushiyama A, Tokunaga F, Asano T, and Sakoda H.
  • Journal Title: Int. J. Mol. Sci. Volume: 18 Issue: 2 Pages: 326-326
  • DOI: 10.3390/ijms18020326
  • URL: https://localhost/en/publications/3031da76-81fd-492f-8585-afdabb4c20b0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice (2016)
  • Author(s): Naznin F, Sakoda H, Okada T, Tsubouchi H, Waise TM, Arakawa K, Nakazato M
  • Journal Title: Eur J Pharmacol Volume: 794 Pages: 37-44
  • DOI: 10.1016/j.ejphar.2016.11.028
  • Peer Reviewed / Open Access
• [Presentation] 神経を介する炎症波及による摂食調節機構の破綻とインスリン抵抗性 (2017)
  • Author(s): 迫田秀之、ナズニン ファーハナ、岡田只士、ワイズ・ティーエム ザベット、十枝内厚次、中里雅光
  • Organizer: 第60回日本糖尿病学会年次学術集会
  • Invited