Crowell Kristen T, Soybel David I, Lang Charles H
Department of Surgery, Penn State College of Medicine, Hershey, Pennsylvania.
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania; and.
Am J Physiol Regul Integr Comp Physiol. 2017 Mar 1;312(3):R388-R399. doi: 10.1152/ajpregu.00498.2016. Epub 2017 Jan 18.
Adipose tissue is an important energy depot and endocrine organ, and the degree of adiposity impacts the host response to infection. However, little is known regarding the mechanisms by which white adipose tissue (WAT) is lost acutely and then restored after the resolution of sepsis. Therefore, the signaling pathways governing protein synthesis, autophagy, apoptosis, and the ubiquitin-proteasome were investigated to identify potential mechanisms mediating the acute (24 h) loss of WAT after cecal ligation and puncture as well as the failure to replenish WAT during recovery (). While whole body fat mass was decreased equally in pair-fed control and septic mice at 5 days after cecal ligation and puncture, fat mass remained 35% lower in septic mice at During sepsis-recovery, protein synthesis in epididymal WAT was increased compared with control values, and this increase was associated with an elevation in eukaryotic translation initiation factor (eIF)2Bε but no change in mammalian target of rapamycin complex 1 activity (eIF4E-binding protein-1 or S6 kinase 1 phosphorylation). Protein breakdown was increased during sepsis-recovery, as evidenced by the elevation in ubiquitin-proteasome activity. Moreover, indexes of autophagy (light chain 3B-II, autophagy-related protein 5/12, and beclin) were increased during sepsis-recovery and associated with increased AMP-activated kinase-dependent Ser-phosphorylated Unc-51-like autophagy activating kinase-1. Apoptosis was increased, as suggested by the increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. These changes were associated with increased inflammasome activity (increased NLR family, pyrin domain containing 3; TMS1; and caspase-1 cleavage) and the endoplasmic reticulum stress response (increased eIF2α and activating transcription factor-4) and browning (uncoupling protein-1) in epididymal WAT. Our data suggest that WAT stores remain depleted during recovery from sepsis due to sustained inflammation and elevations in protein and cellular degradation, despite the increase in protein synthesis.
脂肪组织是一个重要的能量储存库和内分泌器官，肥胖程度会影响宿主对感染的反应。然而，关于白色脂肪组织（WAT）在脓毒症消退后急性丢失然后恢复的机制，我们所知甚少。因此，我们研究了调控蛋白质合成、自噬、凋亡和泛素 - 蛋白酶体的信号通路，以确定介导盲肠结扎和穿刺后WAT急性（24小时）丢失以及恢复期间WAT未能补充的潜在机制。在盲肠结扎和穿刺后5天，成对喂养的对照小鼠和脓毒症小鼠的全身脂肪量均同等程度降低，但在[此处原文缺失具体时间点]时，脓毒症小鼠的脂肪量仍低35%。在脓毒症恢复期间，附睾WAT中的蛋白质合成与对照值相比增加，这种增加与真核翻译起始因子（eIF）2Bε的升高相关，但雷帕霉素靶蛋白复合物1活性（eIF4E结合蛋白 - 1或S6激酶1磷酸化）没有变化。脓毒症恢复期间蛋白质分解增加，泛素 - 蛋白酶体活性升高证明了这一点。此外，自噬指标（轻链3B - II、自噬相关蛋白5/12和贝克林）在脓毒症恢复期间增加，并与AMP激活激酶依赖性丝氨酸磷酸化的Unc - 51样自噬激活激酶 - 1增加相关。凋亡增加，这由半胱天冬酶 - 3和聚（ADP - 核糖）聚合酶的切割增加所表明。这些变化与附睾WAT中炎性小体活性增加（含NLR家族、pyrin结构域的3增加；TMS1；以及半胱天冬酶 - 1切割增加）、内质网应激反应（eIF2α和激活转录因子 - 4增加）和褐变（解偶联蛋白 - 1）相关。我们的数据表明，尽管蛋白质合成增加，但由于持续的炎症以及蛋白质和细胞降解的升高，脓毒症恢复期间WAT储存仍然耗尽。
