Khalyfa Abdelnaby, Poroyko Valeriy A, Qiao Zhuanhong, Gileles-Hillel Alex, Khalyfa Ahamed A, Akbarpour Mahzad, Almendros Isaac, Farré Ramon, Gozal David
Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, United States.
Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain.
Front Physiol. 2017 Nov 2;8:882. doi: 10.3389/fphys.2017.00882. eCollection 2017.
Sleep is an important modulator of metabolic function. Disruptions of sleep in circadian rhythm are common in modern societies and are associated with increased risk of developing cardiometabolic disorders. Exosomes are ubiquitous extracellular vesicles that may play a mechanistic role in metabolic derangements. We hypothesized that alternating dark-light cycles mimicking shift work in mice would alter fecal microbiota and colonic epithelium permeability and alter plasma exosome cargo and metabolic function. C57BL/6 mice were randomly assigned to (i) control day light (CL), or (ii) inverted dark-light every 2 weeks for 8 weeks (IN). Body weight, fat mass and HOMA-IR were measured, along with Tregs, metabolic, and resident macrophages in visceral white adipose tissue (vWAT). Fecal water samples were incubated with confluent colonic epithelium cell cultures in electric cell-substrate impedance sensing (ECIS) arrays, and plasma exosomes were added to differentiated adipocytes and insulin-induced pAKT/AKT expression changes were assessed by western blots. Mice exposed to IN showed elevated HOMA-IR, and their fecal samples showed altered microbiota which promote increased permeability of the colonic epithelial cell barrier. Plasma exosomes decreased pAKT/AKT responses to exogenous insulin compared to CL, and altered expression of circadian clock genes. Inflammatory macrophages (Ly-6c) were increased in IN-exposed vWAT, while Tregs were decreased. Thus, gut microbiota and the cargo of plasma exosomes are altered by periodic shifts in environmental lighting, and effectively alter metabolic function, possibly via induction of systemic inflammation and altered clock expression in target tissues. Further exploration of exosomal miRNA signatures in shift workers and their putative metabolic organ cell targets appears warranted.
睡眠是代谢功能的重要调节因素。昼夜节律性睡眠中断在现代社会很常见,并且与发生心脏代谢紊乱的风险增加有关。外泌体是普遍存在的细胞外囊泡,可能在代谢紊乱中发挥机制性作用。我们假设,模仿小鼠轮班工作的明暗交替周期会改变粪便微生物群和结肠上皮通透性,并改变血浆外泌体货物和代谢功能。将C57BL/6小鼠随机分为(i)对照日光组(CL),或(ii)每2周颠倒一次明暗周期,持续8周(IN)。测量体重、脂肪量和HOMA-IR,以及内脏白色脂肪组织(vWAT)中的调节性T细胞、代谢和常驻巨噬细胞。将粪便水样与电细胞基质阻抗传感(ECIS)阵列中的汇合结肠上皮细胞培养物一起孵育,并将血浆外泌体添加到分化的脂肪细胞中,通过蛋白质印迹法评估胰岛素诱导的pAKT/AKT表达变化。暴露于IN的小鼠显示HOMA-IR升高,其粪便样本显示微生物群改变,这促进了结肠上皮细胞屏障通透性增加。与CL相比,血浆外泌体降低了对外源胰岛素的pAKT/AKT反应,并改变了生物钟基因的表达。在暴露于IN的vWAT中,炎性巨噬细胞(Ly-6c)增加,而调节性T细胞减少。因此,环境光照的周期性变化会改变肠道微生物群和血浆外泌体的货物,并有效改变代谢功能,可能是通过诱导全身炎症和改变靶组织中的生物钟表达。对轮班工作者的外泌体miRNA特征及其假定的代谢器官细胞靶点进行进一步探索似乎是有必要的。