Kusudo Tatsuya, Hashimoto Michihiro, Kataoka Naoya, Li Yongxue, Nozaki Aya, Yamashita Hitoshi
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Department of Nutrition & Food Sciences, Faculty of Human Sciences, Tezukayama Gakuin University, Sakai, Japan.
J Biochem. 2019 Jan 1;165(1):47-55. doi: 10.1093/jb/mvy083.
Brown adipocytes play a critical role for adaptive thermogenesis to regulate body temperature in cold or to circumvent diet-induced obesity. In this study, we investigated the role of cellular repressor of E1A-stimulated genes 1 (CREG1) on brown adipogenesis and uncoupling protein 1 (UCP1) expression by using in vitro culture models. In murine mesenchymal stem cell line C3H10T1/2, Creg1 mRNA expression significantly increased in a time-dependent manner along with Ucp1 mRNA induction in brown adipogenesis. Creg1 gene overexpression upregulated the expression of brown fat-related genes including Ucp1 but its suppression downregulated these gene expression in C3H10T1/2 cells. Unlike the brown adipogenesis, Creg1 mRNA expression decreased significantly after differentiation stimulation in white adipogenesis of 3T3-L1 cells. Either Creg1 gene overexpression or suppression hardly affected white adipogenesis. In addition, CREG1 protein stimulated brown adipogenesis and rescued the adipogenesis in the absence of thyroid hormone in C3H10T1/2 cells. In reporter assay, CREG1 induction stimulated Ucp1 promoter activity, which was enhanced by co-expression with thyroid hormone receptors. The effect of CREG1 on Ucp1 promoter activity was also stimulated by retinoic acid. These results strongly suggest that CREG1 plays an important role on the regulation of UCP1 expression and brown adipogenesis.
棕色脂肪细胞在适应性产热中发挥关键作用，以在寒冷环境中调节体温或预防饮食诱导的肥胖。在本研究中，我们通过体外培养模型研究了E1A刺激基因1细胞抑制因子（CREG1）对棕色脂肪生成和解偶联蛋白1（UCP1）表达的作用。在小鼠间充质干细胞系C3H10T1/2中，在棕色脂肪生成过程中，随着Ucp1 mRNA的诱导，Creg1 mRNA表达呈时间依赖性显著增加。Creg1基因过表达上调了包括Ucp1在内的棕色脂肪相关基因的表达，但其抑制则下调了C3H10T1/2细胞中这些基因的表达。与棕色脂肪生成不同，在3T3-L1细胞的白色脂肪生成中，分化刺激后Creg1 mRNA表达显著降低。Creg1基因的过表达或抑制对白色脂肪生成几乎没有影响。此外，CREG1蛋白刺激棕色脂肪生成，并在C3H10T1/2细胞中在无甲状腺激素的情况下挽救脂肪生成。在报告基因测定中，CREG1诱导刺激Ucp1启动子活性，与甲状腺激素受体共表达可增强该活性。视黄酸也刺激了CREG1对Ucp1启动子活性的作用。这些结果强烈表明，CREG1在UCP1表达和棕色脂肪生成的调节中起重要作用。
