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.

sigma-1 受体 (Sig1R) 是一种独特的配体操作的内质网 (ER) 蛋白，没有任何哺乳动物同源物。长期以来，它一直是干预精神疾病的药理学目标，最近因其神经保护潜力而重新引起人们的兴趣。尽管据报道可调节各种细胞内事件，但其对细胞特性的影响却鲜为人知。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 (MEF) 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）、脂肪生成蛋白（FABP4、ACC1、ACAT2）的蛋白质印迹和脂质的油红-O染色检测诱导的脂肪细胞样表型。我们发现这些蛋白质的诱导上调和脂质积累在Sigmar1 ^-/- (vs Sigmar1 ^+/+ ) MEF 中被严重减轻。用选择性激动剂 (PRE084) 激活 Sig1R 会增加 Sig1R 蛋白并进一步增强Sigmar1 ^{+/+ 中}诱导的脂肪细胞样表型MEF。我们还确定了 6 个月高脂肪饮食诱导的小鼠体重增加，这在Sigmar1 ^-/- (vs Sigmar1 ^+/+ ) 雄性小鼠中受到阻碍。

总之，Sig1R 的基因消融损害，而 Sig1R 的激动剂激活增强了诱导 MEF 的脂肪细胞样表型。在体内，Sig1R 消融阻碍了雄性小鼠在高脂肪饮食中的体重增加。这项研究需要进一步研究 Sig1R 在脂肪细胞分化中的先前未被认识的作用。