Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice.
Caloric restriction decreases ER stress in liver and adipose tissue in ob/ob mice.
复制标题
热量限制可降低 ob/ob 小鼠肝脏和脂肪组织的 ER 应激。
DOI：
10.1016/j.bbrc.2010.11.120
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Araki E
中科院分区：
文献类型：
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作者：
Tsutsumi A;Motoshima H;Kondo T;Kawasaki S;Matsumura T;Hanatani S;Igata M;Ishii N;Kinoshita H;Kawashima J;Taketa K;Furukawa N;Tsuruzoe K;Nishikawa T;Araki E
内质网应激在胰岛素抵抗和糖尿病的发生发展中起着至关重要的作用。虽然卡路里限制(CR)改善了肥胖相关的疾病，但CR对肥胖患者ER应激的影响仍不清楚。为了研究肥胖时CR对内质网应激的影响，ob/ob小鼠被分配到随意(AL)(ob-AL)或CR(ob-CR)喂养(每天2g食物)1-4周。Ob-CR小鼠体重(BW)在2周内降至瘦肉型AL仔鼠水平。Lean-AL和ob-CR小鼠的体重小于ob-AL小鼠。与ob-AL小鼠相比，ob-CR小鼠表现出更好的糖耐量和肝脏胰岛素作用。与瘦肉型AL小鼠相比，ob-AL小鼠肝脏和附睾脂肪中ER应激标记物如磷酸化的PKR样ER激酶(PERK)和真核细胞翻译起始因子2α的水平以及激活转录因子4mRNA的表达水平均显著升高。连续2周和4周的CR显著降低了所有这些标志物的水平，分别低于ob-AL小鼠的35%和50%。CR还显著降低肥胖/肥胖小鼠胰岛素受体底物(IRS)-1和c-Jun氨基末端激酶(JNK)的磷酸化。CR介导的PERK磷酸化水平的降低与4-苯基丁酸的作用相似，后者可减轻体内内质网应激。综上所述，CR通过抑制JNK介导的IRS-1丝氨酸磷酸化，减轻了ob/ob小鼠的内质网应激，改善了肝脏胰岛素的作用。
Endoplasmic reticulum (ER) stress plays a crucial role in the development of insulin resistance and diabetes. Although caloric restriction (CR) improves obesity-related disorders, the effects of CR on ER stress in obesity remain unknown. To investigate how CR affects ER stress in obesity, ob/ob mice were assigned to either ad libitum (AL) (ob-AL) or CR (ob-CR) feeding (2g food/day) for 1–4weeks. The body weight (BW) of ob-CR mice decreased to the level of lean AL-fed littermates (lean-AL) within 2weeks. BW of lean-AL and ob-CR mice was less than that of ob-AL mice. The ob-CR mice showed improved glucose tolerance and hepatic insulin action compared with ob-AL mice. Levels of ER stress markers such as phosphorylated PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2α and the mRNA expression of activating transcription factor 4 were significantly higher in the liver and epididymal fat from ob-AL mice compared with lean-AL mice. CR for 2 and 4weeks significantly reduced all of these markers to less than 35% and 50%, respectively, of the levels in ob-AL mice. CR also significantly reduced the phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun NH2-terminal kinase (JNK) in ob/ob mice. The CR-mediated decrease in PERK phosphorylation was similar to that induced by 4-phenyl butyric acid, which reduces ER stress in vivo. In conclusion, CR reduced ER stress and improved hepatic insulin action by suppressing JNK-mediated IRS-1 serine-phosphorylation in ob/ob mice.