Department of Surgery, University of Wisconsin, Madison, WI 53705, USA.
Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Cell Signal. 2020 Nov;75:109732. doi: 10.1016/j.cellsig.2020.109732. Epub 2020 Aug 2.
The sigma-1 receptor (Sig1R) is a unique ligand-operated endoplasmic reticulum (ER) protein without any mammalian homolog. It has long been a pharmacological target for intervention of psychiatric disorders, and recently garnered refreshed interest for its neuroprotective potential. Though reported to modulate various intracellular events, its influence on cell identity is little known. We explored a role for Sig1R in adipocyte differentiation. We induced adipogenic differentiation of mouse embryonic fibroblasts (MEFs) with a differentiation medium. MEFs were isolated from Sigmar1 and Sigmar1 mice. The induced adipocyte-like phenotype was detected through Western blots of master transcription factors (PPARγ, CEBPA, SREBP1, SREBP2), lipogenic proteins (FABP4, ACC1, ACAT2), and Oil-Red-O staining of lipids. We found that the induced upregulation of these proteins and lipid accumulation were severely mitigated in Sigmar1 (vs Sigmar1) MEFs. Sig1R activation with a selective agonist (PRE084) increased Sig1R protein and further enhanced the induced adipocyte-like phenotype in Sigmar1 MEFs. We also determined mouse body weight gain induced by high-fat diet for 6 months, which was impeded in Sigmar1 (vs Sigmar1) male mice. In summary, genetic ablation of Sig1R impairs, and agonist activation of Sig1R enhances adipocyte-like phenotype of induced MEFs. In vivo, Sig1R ablation impedes the body weight gain of male mice on high-fat diet. This study warrants further investigation of a previously unrecognized role for Sig1R in adipocyte differentiation.
西格玛 1 受体（Sig1R）是一种独特的配体操纵的内质网（ER）蛋白，没有任何哺乳动物同源物。它长期以来一直是干预精神疾病的药理学靶点，最近因其神经保护潜力而重新引起关注。尽管据报道它可以调节各种细胞内事件，但它对细胞身份的影响知之甚少。我们探索了 Sig1R 在脂肪细胞分化中的作用。我们用分化培养基诱导小鼠胚胎成纤维细胞（MEFs）的成脂分化。MEFs 是从 Sigmar1 和 Sigmar1 小鼠中分离出来的。通过主转录因子（PPARγ、CEBPA、SREBP1、SREBP2）、生脂蛋白（FABP4、ACC1、ACAT2）的 Western blot 和油红 O 染色脂质来检测诱导的脂肪细胞样表型。我们发现，这些蛋白的诱导上调和脂质积累在 Sigmar1（与 Sigmar1 相比）MEFs 中严重减轻。用选择性激动剂（PRE084）激活 Sig1R 会增加 Sig1R 蛋白，并进一步增强 Sigmar1 MEFs 中诱导的脂肪细胞样表型。我们还确定了高脂肪饮食 6 个月诱导的小鼠体重增加，Sigmar1（与 Sigmar1 相比）雄性小鼠的体重增加受到阻碍。总之，Sig1R 的基因缺失会损害，而 Sig1R 的激动剂激活会增强诱导的 MEFs 的脂肪细胞样表型。在体内，Sig1R 缺失会阻碍高脂肪饮食雄性小鼠的体重增加。这项研究进一步证明了 Sig1R 在脂肪细胞分化中以前未被认识到的作用。
