Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging
Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging
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DOI：
10.1093/gerona/glu186
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发表时间：
2015-11-01
影响因子：
5.1
通讯作者：
Yung, Raymond
中科院分区：
文献类型：
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作者：
Ghosh, Amiya Kumar;Garg, Sanjay Kumar;Yung, Raymond
脂肪组织炎症与年龄相关的代谢疾病有关。然而，对潜在的机制知之甚少。饮食相关性肥胖中的脂肪组织炎症和胰岛素抵抗与异常内质网（ER）应激有关。这项研究是为了验证我们的假设，增加ER应激反应有助于年龄相关的脂肪组织炎症。我们发现老年（18-20个月）小鼠脂肪组织的ER应激反应高于年轻（4-6个月）小鼠。与年轻的脂肪组织基质细胞相比，在老年脂肪组织基质细胞中观察到ER应激标志物BIP（GRP 78）、CHOP、裂解ATF-6、磷酸化IRE 1 α和XBP- 1升高。此外，老年脂肪组织基质细胞对ER应激诱导剂毒胡萝卜素更敏感。用脂肪组织巨噬细胞进行的类似实验显示，当用毒胡萝卜素诱导时，老年脂肪组织巨噬细胞中Chop和Bip表达升高。化学伴侣4-苯基-丁酸的处理减轻了脂肪组织基质细胞和脂肪组织巨噬细胞中的ER应激，并减弱了来自年轻和老年小鼠的脂肪组织基质细胞的IL- 6和MCP- 1以及脂肪组织巨噬细胞的TNF-α的产生。最后，用4-苯丁酸喂养的老年小鼠减少了ER应激和炎症细胞因子基因的表达。我们的数据表明，衰老脂肪组织中过度的ER应激反应有助于年龄相关的炎症，而这种炎症可以通过化学伴侣治疗来减轻。
Adipose tissue inflammation has been linked to age-related metabolic diseases. However, the underlying mechanisms are poorly understood. Adipose tissue inflammation and insulin resistance in diet associated obesity has been correlated with aberrant endoplasmic reticulum ( ER) stress. This study was undertaken to test our hypothesis that increased ER stress response contributes to age-associated adipose tissue inflammation. We found elevated ER stress response in adipose tissue of old ( 18-20 months) compared to young ( 4-6 months) mice. Elevated ER stress markers BIP ( GRP78), CHOP, cleaved-ATF-6, phospho-IRE1 alpha, and XBP- 1 were observed in old compared to young adipose tissue stromal cells. Additionally, old adipose tissue stromal cells were more sensitive to an ER stress inducer, thapsigargin. Similar experiments with adipose tissue macrophages showed elevated Chop and Bip expression in old adipose tissue macrophages when induced with thapsigargin. Treatment of chemical chaperone 4- phenyle- butyric acid alleviated ER stress in adipose tissue stromal cells and adipose tissue macrophages and attenuated the production of IL- 6 and MCP- 1 by adipose tissue stromal cells, and TNF-alpha by adipose tissue macrophages from both young and old mice. Finally, old mice fed with 4- phenyle- butyric acid have reduced expression of ER stress and inflammatory cytokine genes. Our data suggests that an exaggerated ER stress response in aging adipose tissue contributes to age- associated inflammation that can be mitigated by treatment with chemical chaperones.