Fukunaka Ayako, Fukada Toshiyuki, Bhin Jinhyuk, Suzuki Luka, Tsuzuki Takamasa, Takamine Yuri, Bin Bum-Ho, Yoshihara Toshinori, Ichinoseki-Sekine Noriko, Naito Hisashi, Miyatsuka Takeshi, Takamiya Shinzaburo, Sasaki Tsutomu, Inagaki Takeshi, Kitamura Tadahiro, Kajimura Shingo, Watada Hirotaka, Fujitani Yoshio
Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Laboratory of Developmental Biology & Metabolism, Institute for Molecular & Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
PLoS Genet. 2017 Aug 30;13(8):e1006950. doi: 10.1371/journal.pgen.1006950. eCollection 2017 Aug.
Given the relevance of beige adipocytes in adult humans, a better understanding of the molecular circuits involved in beige adipocyte biogenesis has provided new insight into human brown adipocyte biology. Genetic mutations in SLC39A13/ZIP13, a member of zinc transporter family, are known to reduce adipose tissue mass in humans; however, the underlying mechanisms remains unknown. Here, we demonstrate that the Zip13-deficient mouse shows enhanced beige adipocyte biogenesis and energy expenditure, and shows ameliorated diet-induced obesity and insulin resistance. Both gain- and loss-of-function studies showed that an accumulation of the CCAAT/enhancer binding protein-β (C/EBP-β) protein, which cooperates with dominant transcriptional co-regulator PR domain containing 16 (PRDM16) to determine brown/beige adipocyte lineage, is essential for the enhanced adipocyte browning caused by the loss of ZIP13. Furthermore, ZIP13-mediated zinc transport is a prerequisite for degrading the C/EBP-β protein to inhibit adipocyte browning. Thus, our data reveal an unexpected association between zinc homeostasis and beige adipocyte biogenesis, which may contribute significantly to the development of new therapies for obesity and metabolic syndrome.
鉴于米色脂肪细胞在成年人体内的相关性，对参与米色脂肪细胞生成的分子回路的更好理解为人类棕色脂肪细胞生物学提供了新的见解。锌转运蛋白家族成员SLC39A13/ZIP13的基因突变已知会减少人类的脂肪组织质量；然而，其潜在机制仍不清楚。在这里，我们证明Zip13基因缺陷小鼠表现出增强的米色脂肪细胞生成和能量消耗，并表现出改善的饮食诱导肥胖和胰岛素抵抗。功能获得和功能丧失研究均表明，CCAAT/增强子结合蛋白-β（C/EBP-β）蛋白的积累对于ZIP13缺失导致的脂肪细胞褐变增强至关重要，该蛋白与主要转录共调节因子含PR结构域16（PRDM16）协同作用以确定棕色/米色脂肪细胞谱系。此外，ZIP13介导的锌转运是降解C/EBP-β蛋白以抑制脂肪细胞褐变的先决条件。因此，我们的数据揭示了锌稳态与米色脂肪细胞生成之间意想不到的关联，这可能对肥胖和代谢综合征新疗法的开发做出重大贡献。
