Pathologic endoplasmic reticulum stress induced by glucotoxic insults inhibits adipocyte differentiation and induces an inflammatory phenotype
Pathologic endoplasmic reticulum stress induced by glucotoxic insults inhibits adipocyte differentiation and induces an inflammatory phenotype
复制标题
DOI：
10.1016/j.bbamcr.2016.02.019
复制
发表时间：
2016-06-01
影响因子：
5.1
通讯作者：
Di Jeso, Bruno
中科院分区：
文献类型：
--
作者：
Longo, Michele;Spinelli, Rosa;Di Jeso, Bruno
脂肪细胞分化在肥胖中至关重要。通过控制新的脂肪细胞募集，脂肪形成与脂肪细胞肥大及其不良后果如胰岛素抵抗形成对比。在文献中存在关于内质网（ER）应激和随后的未折叠蛋白反应（UPR）对脂肪细胞分化的影响的对比数据，据报道是必要的或抑制性的。在本研究中，我们试图阐明ER应激和UPR对脂肪细胞分化的影响，我们使用了两种不同的细胞系，广泛使用的前脂肪细胞3 T3-L1细胞和小鼠多能间充质细胞系W20-17细胞。一个强大的ER应激激活剂，毒胡萝卜素，和病理相关的诱导ER应激，氨基葡萄糖（GlcN），诱导ER应激和UPR以上发生在扰动和抑制脂肪细胞分化的情况下。极低浓度的4-苯基丁酸（PBA，一种化学伴侣）仅抑制GlcN引起的ER应激和UPR的过度激活，而不改变分化过程中生理激活的部分，并逆转GlcN对分化的抑制作用。此外，GlcN刺激促炎细胞因子释放，PBA阻止这些作用。NF-κ B的抑制剂也逆转了GlcN对细胞因子释放的影响。这些结果表明，虽然ER应激和UPR活化在脂肪细胞分化过程中被“生理性”活化，但继发于葡萄糖毒性损伤的ER应激活化的“病理性”部分抑制分化。此外，这种代谢损伤导致前脂肪细胞/脂肪细胞群体向促炎表型转变。(C)© 2016 Elsevier B. V.版权所有。
Adipocyte differentiation is critical in obesity. By controlling new adipocyte recruitment, adipogenesis contrasts adipocyte hypertrophy and its adverse consequences, such as insulin resistance. Contrasting data are present in literature on the effect of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) on adipocyte differentiation, being reported to be either necessary or inhibitory. In this study, we sought to clarify the effect of ER stress and UPR on adipocyte differentiation.We have used two different cell lines, the widely used pre-adipocyte 3T3-L1 cells and a murine multipotent mesenchymal cell line, W20-17 cells. A strong ER stress activator, thapsigargin, and a pathologically relevant inducer of ER stress, glucosamine (GlcN), induced ER stress and UPR above those occurring in the absence of perturbation and inhibited adipocyte differentiation. Very low concentrations of 4-phenyl butyric acid (PBA, a chemical chaperone) inhibited only the overactivation of ER stress and UPR elicited by GlcN, leaving unaltered the part physiologically activated during differentiation, and reversed the inhibitory effect of GlcN on differentiation. In addition, GlcN stimulated proinflammatory cytokine release and PBA prevented these effects. An inhibitor of NF-kappa B also reversed the effects of GlcN on cytokine release. These results indicate that while ER stress and UPR activation is "physiologically" activated during adipocyte differentiation, the "pathologic" part of ER stress activation, secondary to a glucotoxic insult, inhibits differentiation. In addition, such a metabolic insult, causes a shift of the preadipocyte/adipocyte population towards a proinflammatory phenotype. (C) 2016 Elsevier B.V. All rights reserved.