Soeda Jumpei, Mouralidarane Angelina, Cordero Paul, Li Jiawei, Nguyen Vi, Carter Rebeca, Kapur Sabrina R, Pombo Joaquim, Poston Lucilla, Taylor Paul D, Vinciguerra Manlio, Oben Jude A
Institute for Liver and Digestive Health, University College London, London, UK.
Division of Women's Health, King's College London, London, UK.
J Physiol Biochem. 2016 Jun;72(2):281-91. doi: 10.1007/s13105-016-0476-6. Epub 2016 Mar 15.
The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults.
非酒精性脂肪性胰腺疾病（NAFPD）的患病率正随着肥胖率的上升而增加。内质网（ER）中与应激相关的改变，如未折叠蛋白反应（UPR），与肥胖有关。本研究的目的是调查成年和围产期饮食诱导肥胖小鼠模型胰腺中的内质网失衡情况。20只雌性C57BL/6J小鼠在怀孕和哺乳前及期间被分配到对照（Con）或致肥胖（Ob）饮食组。它们的后代在产后6个月内断奶并继续喂食Con或Ob饮食。然后，在处死小鼠后，对胰腺进行血浆生化分析、基因表达和蛋白质浓度测定。喂食Ob饮食的小鼠后代体重显著增加（p<0.001），血浆瘦素水平升高（p<0.001），胰岛素水平降低（p<0.01）。母体致肥胖饮食降低了总Eif2α和磷酸化Eif2α水平，并增加了剪接的X盒结合蛋白1（XBP1）。UPR下游调节因子（EDEM、同型半胱氨酸反应性内质网驻留蛋白（HERP）、激活转录因子4（ATF4）和C/EBP同源蛋白（CHOP））以及自噬相关蛋白（LC3BI/LC3BII）的胰腺基因表达在母亲和后代中均因致肥胖喂养而受到不同程度的破坏（p值从<0.1到<0.001）。母体肥胖及其后代的Ob饮食喂养会改变NAFPD中的UPR，涉及促凋亡和自噬相关标志物。在致肥胖损伤后，PERK、IRE1α和ATF6途径的上游和下游调节因子受到的影响各不相同。
