公益財団法人 セコム科学技術振興財団
研究成果報告書研究課題名
亜鉛によるメタボとロコモの予防：亜鉛シグナルの理解による安心で安全な社会を目指して
Prevention of Metabolic Syndrome and Locomotive Syndrome with Zinc: Toward a Safe and Secure
Society through Understanding Zinc Signaling

研究期間
平成３０年 １０月 ～ 令和４年 ９月

報告年月
令和４年 １２月
研究代表者
群馬大学 生体調節研究所 分子糖代謝制御分野 教授
藤谷 与士夫
Laboratory of Developmental Biology and Metabolism, Professor
Yoshio Fujitani, MD,PhD

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Abstract
In Japan, the gap between average life expectancy and healthy life expectancy has become a major social issue. In
particular, locomotive syndrome, which is a risk factor for requiring long-term care, is known to cause deteriorationof motor systems such as bones, joints, and muscles, resulting in impairments in daily activities such as walking,standing, and sitting. It has also been suggested that metabolic syndrome in middle age and beyond is behind theneed for care due to cerebrovascular disease. In other words, preventing locomotive and metabolic syndrome isconsidered extremely important for extending healthy life expectancy.
Previous analyses have revealed that the zinc transporter ZIP13 regulates skeletal muscle and adipocyte functionsbased on the results of studies in humans (EDSSPD3) and mice lacking this transporter activity. In this study, weaimed to answer the questions, "How is the pathophysiology of locomotive syndrome and metabolic syndrome related
to the loss of function of ZIP13, which is involved in the regulation of locomotion and energy metabolism?" Previousstudies have shown that mice lacking the whole body Zip13 gene (Zip13-KO mice) have an ameliorative effect on
metabolic syndrome by increasing browning in white adipose tissue, but it is not clear whether the regulation ofbrowning by ZIP13 is regulated in an adipocyte-autonomous manner. Therefore, we generated mature adipocytespecific Zip13-deficient mice (Zip13Adipo-cKO) and analyzed them, and found that Zip13Adipo-cKO mice exhibit
enhanced lipolysis, preferentially consume lipids, and show resistance to obesity, suggesting a novel ZIP13 function
in lipid metabolism that has not been identified before. Furthermore, the expression of Fth1, a ZIP13-binding protein,
was increased in Zip13Adipo-cKO adipose tissue, and suppression of Fth1 expression reduced lipolysis in Zip13AdipocKO mice, suggesting that a novel pathway, the ZIP13-Fth1 axis, is involved in the regulation of lipolysis.
Zip13-KO mice showed a marked decrease in muscle strength and activity. To investigate the cause of this, wecollected muscle tissue and performed RNAseq and found that myogenesis, muscle contraction, and calcium
signaling were decreased in Zip13-KO mice. Therefore, we evaluated skeletal muscle differentiation potential using
a mouse myoblast cell line C2C12 cells (Zip13-KD cells) and an iPS cell line derived from EDSSPD3 patients, inwhich the Zip13 gene was knocked down, and found that differentiation into skeletal muscle was markedlysuppressed. This suggests that ZIP13-mediated zinc signaling is required for the promotion of skeletal muscle
differentiation. Further tissue-specific functional analysis has revealed that the abnormalities in skeletal muscle
differentiation described above are due to a role for ZIP13 in Pdgfra-positive mesenchymal cells rather than a role
for ZIP13 in MyoD-positive myoblasts, which is now being analyzed in detail.
Next, we analyzed the downstream signals of ZIP13 involved in the induction of beige adipocyte differentiation.
In Zip13-KO cells with enhanced beige adipogenesis, an increase in the protein content of PIAS3 was observed, andat the same time, inhibition of beige adipogenesis was observed when PIAS3 was deleted. This indicates that ZIP13induces beige adipogenesis from progenitor adipocytes by regulating the protein content of PIAS3 through the"ZIP13-PIAS3 axis". Furthermore, we identified regions and amino acid residues important for the binding of PIAS3and ZIP13 within each molecule. Based on this information, we generated a ZIP13 mutant that does not bind toPIAS3 but retains the ability to transport zinc, and introduced it into Zip13-deficient preadipocytes. The mutant was
found to have significantly reduced ability to suppress beige formation by wild-type ZIP13. In other words, direct
association between ZIP13 and PIAS3 was required for ZIP13-mediated beige suppression, suggesting that PIAS32

may be a direct downstream molecule of ZIP13. We are currently analyzing the details of the association mode
between ZIP13 and PIAS3.

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