Longo Michele, Spinelli Rosa, D'Esposito Vittoria, Zatterale Federica, Fiory Francesca, Nigro Cecilia, Raciti Gregory A, Miele Claudia, Formisano Pietro, Beguinot Francesco, Di Jeso Bruno
Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Strada Monteroni, 73100 Lecce, Italy.
Biochim Biophys Acta. 2016 Jun;1863(6 Pt A):1146-56. doi: 10.1016/j.bbamcr.2016.02.019. Epub 2016 Mar 2.
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-kB 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.
脂肪细胞分化在肥胖症中至关重要。通过控制新的脂肪细胞募集，脂肪生成与脂肪细胞肥大及其不良后果（如胰岛素抵抗）形成对比。关于内质网（ER）应激及随后的未折叠蛋白反应（UPR）对脂肪细胞分化的影响，文献中存在相互矛盾的数据，据报道其既有必要性又有抑制作用。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3T3-L1细胞和小鼠多能间充质细胞系W20-17细胞。一种强烈的ER应激激活剂毒胡萝卜素和一种与ER应激病理相关的诱导剂氨基葡萄糖（GlcN），诱导的ER应激和UPR高于未受干扰时发生的水平，并抑制了脂肪细胞分化。极低浓度的4-苯基丁酸（PBA，一种化学伴侣）仅抑制了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，并逆转了GlcN对分化的抑制作用。此外，GlcN刺激促炎细胞因子释放，而PBA可防止这些作用。NF-κB抑制剂也逆转了GlcN对细胞因子释放的影响。这些结果表明，虽然在脂肪细胞分化过程中ER应激和UPR激活是“生理性”激活的，但继发于糖毒性损伤的ER应激激活的“病理性”部分会抑制分化。此外，这种代谢损伤会使前脂肪细胞/脂肪细胞群体向促炎表型转变。
