The function and therapeutic application of macrophage-specific H-ferritin in chronic inflammation of obese adipose tissue

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08480
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: The University of Tokushima
• Principal Investigator: IKEDA Yasumasa 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (60432754)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 鉄 / マクロファージ

Outline of Final Research Achievements

We investigated the role of macrophage H-ferritin in obesity and diabetes using conditional macrophage-specific H-ferritin knockout (LysM-Cre Fth KO) mice. Iron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from KO mice. HFD-induced obesity was lower in KO mice with the reduced mRNA expression of inflammatory cytokines, infiltrated macrophages and oxidative stress in the adipose tissue than WT mice. WT mice fed HFD had elevated iron concentration in fat and spleen, which was not observed in KO mice fed an HFD. Impaired both glucose tolerance and insulin sensitivity by HFD was alleviated in KO mice. Additionally, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. The findings from this study highlight macrophage iron levels involves in the development of obesity and diabetes through regulating inflammatory response and energy metabolism in adipose tissue.

Free Research Field

循環代謝薬理学

Academic Significance and Societal Importance of the Research Achievements

健康長寿のための栄養素の重要性、特に微量元素についての研究が進展するにつれて新しい知見が次々と明らかにされている。鉄摂取量や生体内鉄量が多いと様々な疾患のリスクが高まることが報告されており、鉄摂取が病態をむしろ悪化させることが危惧される。その一方で、生体内鉄量を減らすことで病態の改善が得られるも、従来の除鉄は非特異的あり限界があった。本研究によって、マクロファージ鉄が慢性炎症制御の標的であること、FTHが新規の鉄制御標的遺伝子であることが明らかとなり、マクロファージ特異的に鉄除去可能な新たな治療法の創出へと応用・展開につながると考えられる。