The role of hypothalamic orexin system in prevention of non-alcoholic steatohepatitis and hepatocellular carcinoma in diet-induced obesity

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19704
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
• Research Institution: University of Toyama
• Principal Investigator: TSUNEKI Hiroshi 富山大学, 学術研究部薬学・和漢系, 教授 (20332661)
• Co-Investigator(Kenkyū-buntansha): 笹岡 利安 富山大学, 学術研究部薬学・和漢系, 教授 (00272906)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 非アルコール性脂肪肝炎 / 肝細胞癌 / 肥満 / 視床下部 / オレキシン

Outline of Final Research Achievements

We investigated the role of hypothalamic orexin system regulating whole-body glucose and energy metabolism in prevention of obesity-induced development of non-alcoholic steatohepatitis (NASH). Orexin knockout mice showed severe obesity and progression of NASH and hepatocellular carcinoma (HCC) during long-term exposure to high fat diet feeding. Supplementation of orexin A prevented the key process of NASH development (i.e., endoplasmic reticulum stress and chronic inflammation in the liver) under the diet-induced obese conditions. These results suggest that central orexin system is a crucial therapeutic target for preventing NASH and HCC. Thus, orexin knockout mice are considered to be a useful animal model for the research to establish novel drug therapy against NASH and HCC.

Free Research Field

糖尿病・内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

本研究では、オレキシンの中枢作用が肥満に伴うNASHや肝細胞癌の防止に必須の役割を果たすことを見出し、脳のオレキシン神経系がNASH治療法の開発分野における新規標的であるとの概念を提起した。また、高脂肪食負荷オレキシン欠損マウスは、現代人特有の脂質摂取過剰、運動不足、および自律神経障害の複合効果に起因するNASH/肝細胞癌の病態モデル動物として、今後の治療法開発に有用であることを示した。