Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss.
Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss.
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作者：
Gregor MF;Yang L;Fabbrini E;Mohammed BS;Eagon JC;Hotamisligil GS;Klein S
肥胖症与胰岛素抵抗和2型糖尿病有关，尽管这些病理学联系的机制尚未确定。最近在啮齿动物模型中的研究揭示了脂肪和肝脏组织中的内质网（ER）应激，并证明ER应激可引起胰岛素抵抗。因此，我们测试了这些应激途径是否也存在于肥胖的人类受试者中和/或受体重减轻的调节。研究设计和方法：11名肥胖男性和女性（BMI 51.3 ± 3.0 kg/m2）在胃旁路手术（GBP）前和手术后1年进行研究。我们在手术前后用高胰岛素-正葡萄糖钳夹技术检测全身胰岛素敏感性，并收集皮下脂肪和肝脏组织检测ER应激标志物。GBP手术后1年，受试者体重减轻39 ± 9%（P < 0.001），这与肝脏、骨骼肌和脂肪组织胰岛素敏感性的显著改善有关。脂肪组织中ER应激标志物随体重减轻而显著降低。具体而言，葡萄糖调节蛋白78（Grp 78）和剪接的X-box结合蛋白-1（sXBP-1）mRNA水平降低，磷酸化延伸起始因子2α（eIF 2 α）和应激激酶c-Jun NH 2-末端激酶1（JNK 1）也降低（所有P值均<0.05）。一部分受试者的肝脏切片在手术前显示Grp 78和磷酸化eIF 2 α的强染色，在GBP后切片中减少。结论：这项研究提供了重要的证据，表明ER应激途径存在于肥胖人群的选定组织中，并且这些信号受到显著的体重减轻和代谢改善的调节。因此，这表明肥胖相关的ER应激和肥胖人群的代谢功能障碍之间存在关系的可能性。
OBJECTIVE—Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS—Eleven obese men and women (BMI 51.3 ± 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers. RESULTS—Subjects lost 39 ± 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2α (eIF2α) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2α before surgery, which was reduced in post-GBP sections. CONCLUSIONS—This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.
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影响因子：
5.8
作者：
Bastard, JP;Jardel, C;Hainque, B
通讯作者：
Hainque, B
DOI：
10.1016/j.soard.2005.04.002
发表时间：
2005-05-01
期刊：
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery
影响因子：
--
作者：
Buchwald, Henry
通讯作者：
Buchwald, Henry
影响因子：
56.9
作者：
Özcan, U;Cao, Q;Hotamisligil, GS
通讯作者：
Hotamisligil, GS
影响因子：
8.2
作者：
Laybutt, D. R.;Preston, A. M.;Biden, T. J.
通讯作者：
Biden, T. J.
影响因子：
56.9
作者：
Oezcan, Umut;Yilmaz, Erkan;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.