Circulating exosomes and gut microbiome induced insulin resistance in mice exposed to intermittent hypoxia: Effects of physical activity

Abstract

Background 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. Methods 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. Findings 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). Interpretation 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. Funding 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.

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

“…Tightening the intestinal mucosal barrier also plays an important role in suppressing systemic inflammation and consequent neuroinflammation. Numerous results suggest that the gut microbiome modulate the intestinal barrier function [149][150][151]. In this context, butyrate has been shown to enhance the intestinal barrier function through maintenance of the expression of tight junction proteins including claudins, occludin, and zonula occludens protein-1 (ZO-1) [152], and an animal study has demonstrated that oral administration of C. butyricum or butyrate reduces intestinal injury associated with severe acute pancreatitis [153].…”

Cell-Selective Altered Cargo Properties of Extracellular Vesicles Following In Vitro Exposures to Intermittent Hypoxia

“…Furthermore, the ratio of pAKT/tAKT as indicator of insulin sensitivity remained unaltered after exposure to any of the EVs, irrespective of whether the cells had been exposed to IH or RA. Such findings, which are not aligned with the fact that circulating EVs in patients with OSA induce insulin resistance [ 21 , 55 ], suggest that other cells (for example, platelets, lymphocytes, etc.) and possibly other factors that are present in OSA but not reflected in the in vitro IH exposures (e.g., sleep fragmentation) may be operationally involved.…”

“…A number of studies have highlighted the potential contributions of EVs to human diseases, and OSA is not an exception. Studies on the involvement of EVs in the emergence of endothelial cell dysfunction and adipocyte insulin resistance in both patients suffering from OSA and animal models of OSA have provided robust initial evidence supporting such critical roles [ 9 , 21 , 28 , 55 , 64 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. EV cargo is altered in response to hypoxia.…”

Role and Treatment of Insulin Resistance in Patients with Chronic Kidney Disease: A Review

“…This alteration causes intestinal barrier dysfunction, secretory deficiency of incretin in the intestine, and activation of chronic inflammation. These changes worsen the conditions of IR and cause NAFLD and diabetes mellitus [64][65][66]. Short-chain fatty acids produced by the breakdown of dietary fiber caused by intestinal bacteria promote energy consumption and increase appetite-suppressing hormones [67].…”