Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, 31151, Republic of Korea.
Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si 31151, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2021 May 1;1867(5):166099. doi: 10.1016/j.bbadis.2021.166099. Epub 2021 Feb 6.
Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.
内质网（ER）应激与各种代谢疾病密切相关，如肥胖和糖尿病。米色/棕色脂肪细胞的发育增加了产热，有助于减少肥胖。尽管已经研究了 ER 应激与白色脂肪细胞之间的关系，但 ER 应激和未折叠蛋白反应（UPR）诱导在米色脂肪细胞分化中的可能作用仍有待研究。在这项研究中，我们研究了 ER 应激如何在体外和体内影响米色脂肪细胞分化。在米色脂肪细胞分化的早期阶段（第 2 天），eIF2α 的磷酸化短暂降低，而在晚期阶段则伴随着 C/EBP 同源蛋白（CHOP）的诱导而被诱导。CHOP 的强制表达抑制了米色脂肪细胞标记物的表达，包括 Ucp1、Cox8b、Cidea、Prdm16 和 Pgc-1α，随后诱导了米色脂肪细胞分化。当通过化学伴侣牛磺熊脱氧胆酸（TUDCA）减少 ER 应激时，解偶联蛋白 1（UCP1）的米色脂肪细胞标记物的表达在腹股沟白色脂肪组织（iWAT）中显著增强，高脂肪饮食（HFD）诱导的异常代谢表型得到改善。总之，我们发现 ER 应激和 UPR 诱导与米色脂肪生成密切相关。这些结果表明，通过激活 iWAT 棕色化来调节 ER 应激可能是一种针对代谢功能障碍的潜在治疗干预措施。
