The elucidation of the beige determination mechanism via biometal transporter

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08971
• 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: Gunma University
• Principal Investigator: Ayako Fukunaka 群馬大学, 生体調節研究所, 助教 (60586402)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 脂質代謝 / 金属輸送体 / 鉄 / 脂肪分解 / 肥満治療

Outline of Final Research Achievements

We have previously reported that the zinc transporter ZIP13, a protein associated with recessive human connective tissues disorders, negatively regulates the adipocyte browning pathway (Fukunaka A., et al., PLoS Genet., 2017). Here, we report the metabolic phenotypes of adipocyte-specific Zip13-deficient (Adipo-Zip13-KO) mice. These mice showed little adipocyte browning phenotypes, suggesting that promotion of adipocyte browning by Zip13 deficiency may occur at an earlier timepoint than Adiponectin expression. On the other hand, Adipo-Zip13-KO mice showed accelerated lipolysis in adipocytes, leading to reduced respiratory exchange ratios (RER) and resistance against high-fat diet-induced obesity. Furthermore, ZIP13 mainly mobilized iron in mature adipocytes, and this ZIP13-mediated iron contributed to the inhibition of lipolysis.
These results suggest that the ZIP13-iron axis is a new regulatory mechanism for lipolysis, which might be a new therapeutic target for obesity.

Free Research Field

代謝

Academic Significance and Societal Importance of the Research Achievements

肥満は増加の一途をたどっており、その病態の解明と新規治療薬の開発は急務である。脂肪組織は外部環境を感知して応答し、エネルギーの貯蔵や消費を調節する非常に動的な臓器であるため、脂肪細胞の性質や機能を制御することが肥満改善の最も有効な手段の一つとして期待されている。
本研究により、ZIP13は成熟脂肪細胞においては細胞内の鉄量を変化させて、脂肪分解を抑制する新規の機能を持つことが明らかとなり、ZIP13は細胞分化に伴い亜鉛と鉄を使い分けるという、新しいコンセプトが提唱できる。また、ZIP13を成熟脂肪細胞特異的に阻害することで、エーラス・ダンロス症候群を示さず、肥満治療に繋がる可能性が考えられた。