scholarly journals Effects of Chronic Intermittent Hypoxia and Chronic Sleep Fragmentation on Gut Microbiome, Serum Metabolome, Liver and Adipose Tissue Morphology

2021 ◽  
Author(s):  
Fan Wang ◽  
Juanjuan Zou ◽  
Huajun Xu ◽  
Weijun Huang ◽  
Xiaoman Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Intermittent Hypoxia ◽  
Synergistic Effects ◽  
Sleep Fragmentation ◽  
Chronic Intermittent Hypoxia ◽  
Intestinal Microbes ◽  
Tissue Morphology ◽  
Obstructive Sleep ◽  
Chronic Sleep

Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as Akkermansia mucinphila, Clostridium spp., Lactococcus spp., and Bifidobacterium spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.

scholarly journals Intermittent Hypoxia Mediates Caveolae Disassembly That Parallels Insulin Resistance Development

2020 ◽  
Vol 11 ◽  
Author(s):  
Maider Varela-Guruceaga ◽  
Elise Belaidi ◽  
Lucie Lebeau ◽  
Ella Aka ◽  
Ramaroson Andriantsitohaina ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Intermittent Hypoxia ◽  
Molecular Mechanisms ◽  
Chronic Intermittent Hypoxia ◽  
Resistance Development ◽  
Systemic Insulin Resistance ◽  
Obstructive Sleep ◽  
Protein Expressions ◽  
Resistance State

Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients.

scholarly journals Chronic Intermittent Hypoxia Induces Early-Stage Metabolic Dysfunction Independently of Adipose Tissue Deregulation

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1233
Author(s):  
Fátima O. Martins ◽  
Joana F. Sacramento ◽  
Elena Olea ◽  
Bernardete F. Melo ◽  
Jesus Prieto-Lloret ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Intermittent Hypoxia ◽  
Early Stage ◽  
Tissue Hypoxia ◽  
Whole Body ◽  
Chronic Intermittent Hypoxia ◽  
Adipose Tissue Dysfunction ◽  
Obstructive Sleep

Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism.

scholarly journals Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia

2021 ◽  
Author(s):  
Mohammad Badran ◽  
Bisher Abuyassin ◽  
Najib Ayas ◽  
Don D. Sin ◽  
Ismail Laher
Keyword(s):  
Obstructive Sleep Apnea ◽  
Chronic Condition ◽  
Intermittent Hypoxia ◽  
Kidney Diseases ◽  
Chronic Intermittent Hypoxia ◽  
Telomere Shortening ◽  
Chronic Kidney Diseases ◽  
Biomarkers Of Aging ◽  
Obstructive Sleep ◽  
Renal Aging

AbstractObstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). There is increased biomarkers of aging, such as telomere shortening, in patients with OSA. We assessed telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH using a PCR protocol, and demonstrate significant telomere shortening in both tissues. This data indicates that IH, a hallmark of OSA, can accelerate vascular and renal aging that may contribute to OSA-induced CVD and CKD

scholarly journals Tempol Alleviates Chronic Intermittent Hypoxia-Induced Pancreatic Injury Through Repressing Inflammation and Apoptosis

2019 ◽  
pp. 445-455
Author(s):  
Y. WANG ◽  
L. AI ◽  
B. HAI ◽  
Y. CAO ◽  
R. LI ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Pancreatic Injury ◽  
Protective Role ◽  
Pancreatic Tissue ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Intermittent Hypoxia ◽  
Obstructive Sleep ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Oxide Synthase

Obstructive sleep apnea (OSA) has been demonstrated to be implicated in disorder of insulin secretion and diabetes mellitus. In this study, we aimed to evaluate the protective role of tempol, a powerful antioxidant, in chronic intermittent hypoxia (IH)-induced pancreatic injury. The rat model of OSA was established by IH exposure. The pathological changes, increased blood-glucose level, and raised proinsulin/insulin ratio in pancreatic tissues of rats received IH were effectively relieved by tempol delivery. In addition, the enhanced levels of pro-inflammatory cytokines, TNF-α, IL-1β, IL-6, and inflammatory mediators, PGE2, cyclooxygenase-2 (COX-2), NO, and inducible nitric oxide synthase (iNOS) in pancreatic tissue were suppressed by tempol. Moreover, tempol inhibited IH-induced apoptosis in pancreatic tissue as evidenced by upregulated Bcl-2 level, and downregulated Bax and cleaved caspase-3 levels. Finally, the abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways induced by IH was restrained by tempol administration. In summary, our study demonstrates that tempol relieves IH-induced pancreatic injury by inhibiting inflammatory response and apoptosis, which provides theoretical basis for tempol as an effective treatment for OSA-induced pancreatic injury.

scholarly journals Differential effect of intermittent hypoxia and sleep fragmentation on PD-1/PD-L1 upregulation

SLEEP ◽  
2019 ◽  
Vol 43 (5) ◽  
Author(s):  
Carolina Cubillos-Zapata ◽  
Isaac Almendros ◽  
Elena Díaz-García ◽  
Victor Toledano ◽  
Raquel Casitas ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Cd8 T Cells ◽  
Intermittent Hypoxia ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Sleep Fragmentation ◽  
Murine Splenocytes ◽  
In Vivo Models ◽  
Obstructive Sleep

Abstract Immunosurveillance is compromised in patients with obstructive sleep apnea (OSA) as reflected by overexpression of the programmed death cell receptor and its ligand (PD-1/PD-L1) coinhibitory axis. However, the contributions of intermittent hypoxia (IH) and sleep fragmentation (SF) are unclear. We therefore evaluated the expression of PD-1 and PD-L1 on immune cells from mice subjected to IH or SF, and in human cells exposed to IH, oxidative stress, or both conditions. Six-week-old male C57BL/6J mice were exposed to either IH or SF using previously established in vivo models. Moreover, human peripheral blood mononuclear cells (PBMC) were cultured overnight under normoxia, IH, hydrogen peroxide (H2O2), or both. Murine splenocytes and human PBMC were isolated, and labeled using surface-specific antibodies for flow cytometry analysis. Compared to control mice, IH induced higher expression of PD-L1 on F4/80 cells and of PD-1 on CD4+ and CD8+ T-cells, whereas no significant changes emerged after SF. In vitro models of IH and oxidative stress showed similar changes for expression of PD-L1 on human monocytes and PD-1 on CD4+ T-cells. Furthermore, H2O2 increased PD-1 expression on CD8+ T-cells, compromising their cytotoxic capacity assessed by perforin expression, similar to IH. No evidence of synergistic effects was apparent. Therefore, PD-1/PD-L1 upregulation reported in patients with OSA appears to be preferentially mediated by IH rather than SF.

Chronic intermittent hypoxia impairs diuretic and natriuretic responses to volume expansion in rats with preserved low-pressure baroreflex control of the kidney

2021 ◽  
Vol 320 (1) ◽  
pp. F1-F16
Author(s):  
Sara AlMarabeh ◽  
Julie O’Neill ◽  
Jeremy Cavers ◽  
Eric F. Lucking ◽  
Ken D. O’Halloran ◽  
...  
Keyword(s):  
High Pressure ◽  
Volume Expansion ◽  
Intermittent Hypoxia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Low Pressure ◽  
Chronic Intermittent Hypoxia ◽  
Transient Receptor Potential Vanilloid ◽  
Baroreflex Control ◽  
Obstructive Sleep

We examined the effects of exposure to chronic intermittent hypoxia (CIH) on baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory responses to volume expansion (VE) before and after intrarenal transient receptor potential vanilloid 1 (TRPV1) blockade by capsaizepine (CPZ). Male Wistar rats were exposed to 96 cycles of hypoxia per day for 14 days (CIH) or normoxia. Urine flow and absolute Na+ excretion during VE were less in CIH-exposed rats, but the progressive decrease in RSNA during VE was preserved. Assessment of the high-pressure baroreflex revealed an increase in the operating and response range of RSNA and decreased slope in CIH-exposed rats with substantial hypertension [+19 mmHg basal mean arterial pressure (MAP)] but not in a second cohort with modest hypertension (+12 mmHg). Intrarenal CPZ caused diuresis, natriuresis, and a reduction in MAP in sham-exposed (sham) and CIH-exposed rats. After intrarenal CPZ, diuretic and natriuretic responses to VE in CIH-exposed rats were equivalent to those of sham rats. TRPV1 expression in the renal pelvic wall was similar in both experimental groups. Exposure to CIH did not elicit glomerular hypertrophy, renal inflammation, or oxidative stress. We conclude that exposure to CIH 1) does not impair the low-pressure baroreflex control of RSNA; 2) has modest effects on the high-pressure baroreflex control of RSNA, most likely indirectly due to hypertension; 3) can elicit hypertension in the absence of kidney injury; and 4) impairs diuretic and natriuretic responses to fluid overload. Our results suggest that exposure to CIH causes renal dysfunction, which may be relevant to obstructive sleep apnea.

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