Elucidation of the molecular mechanism of excessive fructose intake-induced metabolic disorders using fatty acid synthase-deficient mice

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K17790
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Matsukawa Toshiya 国立研究開発法人国立国際医療研究センター, その他部局等, 研究員 (00817653)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: フルクトース / 肝臓 / 2型糖尿病 / 非アルコール性脂肪性肝疾患 / インスリン抵抗性 / 脂肪酸合成酵素 / シグナル伝達 / Western diet

Outline of Final Research Achievements

In this study, we evaluated the role of fatty acid synthase (FAS), which plays a central role in de novo lipogenesis, in high sucrose high fat diet (HSHF diet)-induced obesity and type 2 diabetes.
Firstly, we generated liver-specific FAS-deficient mice. Mice were fed with the HSHF diet to induce obesity and type 2 diabetes. In the results, the insulin resistance, fatty liver, and liver damage induced by the HSHF diet were ameliorated by the FAS deficiency. At this time, the insulin signaling in the liver and skeletal muscle were enhanced. Furthermore, tamoxifen-induced liver-specific FAS-deficient mice showed that insulin resistance and fatty liver improved when FAS was deficient after pathogenesis, indicating a therapeutic effect of subacute FAS deficiency.
These results indicate that inhibition of FAS may be a potential therapeutic target for the treatment of Western-style obesity, which has been on the rise in Japan in recent years.

Free Research Field

栄養生理学

Academic Significance and Societal Importance of the Research Achievements

フルクトースの過剰摂取によって引き起こされるインスリン抵抗性や脂肪肝などを症状とする脂肪肝合併2型糖尿病は脂肪酸合成酵素の阻害で治療・改善できることから、脂肪酸合成酵素の抑制は近年我が国で増加にある欧米型肥満に対する治療標的となる可能性を示している。