Sigma-1 receptor ablation impedes adipocyte-like differentiation of mouse embryonic fibroblasts

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.