Department of Child Health and the Child Health Research Institute, University of Missouri, School of Medicine, Columbia, 400N. Keene Street, Suite 010, MO 65201, United States.
University of Missouri Metagenomics Center, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri at Columbia, Columbia, MO 65201, United States.
EBioMedicine. 2021 Feb;64:103208. doi: 10.1016/j.ebiom.2021.103208. Epub 2021 Jan 21.
Gut microbiota (GM) contribute to obesity and insulin resistance (IR). Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), promotes IR and alters GM. Since circulating exosomes are implicated in IR, we examined the effects of IH and physical activity (PA) in mice on GM, colonic epithelium permeability, systemic IR, and plasma exosome cargo, and exosome effects on visceral white adipose tissues (vWAT) IR.
C57BL/6 mice were exposed to IH or room air (RA) for 6 weeks with and without PA (n = 12/group), and GM and systemic IR changes were assessed, as well as the effects of plasma exosomes on naïve adipocyte insulin sensitivity. Fecal microbiota transfers (FMT) were performed in naïve mice (n = 5/group), followed by fecal 16S rRNA sequencing, and systemic IR and exosome-induced effects on adipocyte insulin sensitivity were evaluated.
Principal coordinate analysis (PCoA) ordinates revealed B-diversity among IH and FMT recipients that accounted for 64% principal component 1 (PC1) and 12.5% (PC2) of total variance. Dominant microbiota families and genera in IH-exposed and FMT-treated were preserved, and IH-exposed GM and IH-FMT induced increased gut permeability. Plasma exosomes from IH-exposed and IH-FMT mice decreased pAKT/AKT responses to exogenous insulin in adipocytes vs. IH+PA or RA FMT-treated mice (p = 0.001).
IH exposures mimicking OSA induce changes in GM, increase gut permeability, and alter plasma exosome cargo, the latter inducing adipocyte dysfunction (increased IR). Furthermore, these alterations improved with PA. Thus, IH leads to perturbations of a singular GM-circulating exosome pathway that disrupts adipocyte homeostasis resulting in metabolic dysfunction, as reflected by IR.
This study was supported by grants from the National Institutes of Health grants HL130984 and HL140548 and University of Missouri Tier 2 grant. The study has not received any funding or grants from pharmaceutical or other industrial corporations.
肠道微生物群（GM）有助于肥胖和胰岛素抵抗（IR）。阻塞性睡眠呼吸暂停（OSA）以间歇性缺氧（IH）为特征，可促进 IR 并改变 GM。由于循环外泌体与 IR 有关，我们研究了 IH 和运动（PA）对 GM、结肠上皮通透性、全身 IR 和血浆外泌体负荷的影响，以及外泌体对内脏白色脂肪组织（vWAT）IR 的影响。
将 C57BL/6 小鼠暴露于 IH 或室内空气（RA）中 6 周，同时进行和不进行 PA（每组 n=12），并评估 GM 和全身 IR 的变化，以及血浆外泌体对幼稚脂肪细胞胰岛素敏感性的影响。在幼稚小鼠中进行粪便微生物群转移（FMT）（每组 n=5），然后进行粪便 16S rRNA 测序，并评估全身 IR 和外泌体对脂肪细胞胰岛素敏感性的影响。
主坐标分析（PCoA）坐标揭示了 IH 和 FMT 接受者之间的 B 多样性，占总第 1 主成分（PC1）的 64%和第 2 主成分（PC2）的 12.5%。暴露于 IH 和接受 FMT 治疗的优势微生物群家族和属得以保留，IH 暴露的 GM 和 IH-FMT 诱导肠道通透性增加。与 IH+PA 或 RA-FMT 治疗的小鼠相比，来自 IH 暴露和 IH-FMT 小鼠的血浆外泌体降低了外源性胰岛素对脂肪细胞的 pAKT/AKT 反应（p=0.001）。
模拟 OSA 的 IH 暴露会导致 GM 发生变化，增加肠道通透性，并改变血浆外泌体负荷，后者会导致脂肪细胞功能障碍（IR 增加）。此外，这些变化可以通过 PA 得到改善。因此，IH 导致单一 GM-循环外泌体途径的扰动，破坏脂肪细胞稳态，导致代谢功能障碍，如 IR 所示。
本研究得到美国国立卫生研究院拨款 HL130984 和 HL140548 以及密苏里大学 Tier 2 拨款的支持。该研究没有得到制药或其他工业公司的任何资金或拨款。
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