Jian Guan

Sleep disruption in obstructive sleep apnea syndrome is characterized by frequent microarousals and reduced sleep depth, yet the underlying mechanisms remain unclear. Here, we show that intermittent hypercapnic air (HA) induces time-locked microarousals, fragments sleep, reduces non–rapid eye movement (NREM) sleep depth, and diminishes rapid eye movement (REM) sleep. HA exposure activates glutamatergic neurons in the nucleus tract solitary (NTS ^Vglut2 ), and their optogenetic or chemogenetic activation is sufficient to trigger arousal and impair sleep. Projection-specific activation reveals that NTS ^Vglut2 projections to the paraventricular nucleus (PVN), parabrachial nucleus (PB), paraventricular thalamus, and locus coeruleus (LC) promote arousal, whereas projections to the PB and LC additionally reduce NREM sleep depth. Inhibition of NTS ^Vglut2 projection to the PVN significantly postpones HA-induced arousal. NTS ^Vglut2 terminals monosynaptically activate corticotropin-releasing hormone neurons in the PVN (PVN ^CRH ), and inhibition of PVN ^CRH neurons or knockdown of Slc17a6 (encoding Vglut2), but not Crh , delays hypercapnia-induced arousal. These findings identify neural circuits underlying hypercapnia-induced microarousal and reduced sleep depth.

Background: BTB domain containing 9 (BTBD9) is among the most reproducible genetic risk factors for sleep-related disorders, yet its molecular function in sleep regulation remains unclear. Here, we aimed to define the downstream substrate, core brain region, and molecular mechanism through which BTBD9 regulates sleep–wake homeostasis. Methods: Population-scale genomic and brain expression quantitative trait locus (eQTL) datasets were integrated to infer the direction of BTBD9 -associated genetic risk in sleep-related traits. Basal forebrain-specific neuronal manipulation of Btbd9 was combined with electroencephalography/electromyography (EEG/EMG)-based sleep analysis and fiberphotomerty to define the relevant brain locus and functional output. Ubiquitinomics, protein interaction, ubiquitination, and enzymatic assays were used to identify BTBD9-regulated substrates and determine how BTBD9 -dependent modification affects metabolic enzyme activity. Basal forebrain-specific genetic disruption, receptor pharmacology, and adeno-associated virus (AAV)-delivered interfering peptides were further applied to test pathway necessity and reversibility in vivo. Results: human genetic analyses showed that BTBD9 variants associated with higher expression predicted a pro-arousal tendency. Consistently, neuron-specific deletion of Btbd9 in the mouse basal forebrain increased non-rapid eye movement (NREM) sleep and extracellular adenosine levels. Mechanistically, IMPDH2, the rate-limiting enzyme in de novo purine biosynthesis, was identified as a substrate of the Cullin-RING E3 ubiquitin ligase 3 (CRL3) ^BTBD9 ubiquitin ligase. BTBD9-mediated ubiquitination at IMPDH2 lysine 195 (K195) relieved guanosine triphosphate (GTP)-dependent allosteric inhibition, thereby limiting adenosine accumulation and sleep pressure. Basal forebrain neuronal knockout of Impdh2 recapitulated the sleep-promoting effect of Btbd9 deletion, whereas adenosine A1 receptor (A1R) blockade attenuated this phenotype. AAV-delivered interfering peptides targeting the BTBD9–IMPDH2 interaction reduced IMPDH2 ubiquitination, elevated adenosine levels, increased NREM sleep, and rescued BTBD9 overexpression-induced abnormal wakefulness in vivo. Conclusions: These findings identify a BTBD9–IMPDH2–adenosine pathway that links human genetic risk to basal forebrain control of sleep homeostasis. By defining BTBD9 as a molecular regulator of purine metabolism, this study provides a mechanistic framework for understanding and potentially targeting BTBD9 -related sleep dysregulation.

Background: Sleep fragmentation impairs health and quality of life, yet its relationship with glucose–lipid metabolic dysregulation remains unclear. This study investigated this association in obstructive sleep apnea (OSA), with a focus on nocturnal hypoxia and hypoxia-related brainstem cellular responses. Methods: This large-scale cross-sectional study included 5,885 adults with suspected OSA from the Shanghai Sleep Health Study. Glucose–lipid metabolic status was assessed using the triglyceride–glucose (TyG) index, TyG-body mass index (TyG-BMI), metabolic score for insulin resistance (METS-IR), and metabolic syndrome. Sleep fragmentation was quantified by the micro-arousal index (MAI). Multivariable regression, restricted cubic spline, threshold effect, multiplicative and additive interaction, stratified analyses, Benjamini–Hochberg false discovery rate (FDR) correction were performed. GEO single-nucleus analyses were conducted to explore intermittent hypoxia-related cellular and metabolic pathway responses in the brainstem (metabolic activity scoring, GSVA, scTenifoldKnk). Results: TyG, TyG-BMI, and METS-IR were independently positively associated with MAI. Each 1-unit increase in TyG was associated with a 4.0-unit increase in MAI ( β = 4.0, p < 0.001). TyG-BMI and METS-IR showed significant nonlinear dose–response relationships with thresholds at 310.31 and 57.25, respectively. OSA severity and nocturnal hypoxia significantly strengthened these associations through both multiplicative and additive interactions. When AHI > 5, the associations of TyG ( β = 4.04), TyG-BMI (β = 0.08), and METS-IR (β = 0.41) on MAI were more pronounced. Combined exposure was associated with 4.07–5.91-fold higher odds of elevated MAI. All primary associations remained significant after FDR correction. Single-nucleus analyses suggested widespread glucose–lipid metabolic reprogramming in brainstem cells, particularly neurons and oligodendrocytes. Conclusion: Glucose–lipid metabolic abnormalities were significantly associated with OSA-related sleep fragmentation, and these associations were stronger among participants with greater OSA severity and nocturnal hypoxia.

Metabolic comorbidities related to obstructive sleep apnoea (OSA) are a major concern in regarding OSA prognosis and complexity. However, few studies have investigated the interrelationships among these metabolic comorbidities. We explored the associations among insulin resistance (IR), the waist-to-hip ratio (WHR), and OSA using innovative and rigorous statistical methods. We enrolled 5,326 subjects after meticulous recording anthropometric, biochemical, and standard polysomnographic parameters. The relationships among IR, WHR, and OSA were analyzed using confirmatory factor analysis (CFA) as well as moderation and mediation analyses. CFA showed that IR and obesity were strongly correlated (loading = 0.73, p < 0.001). OSA was associated with both obesity and IR (loading = 0.57, p < 0.001; loading = 0.46, p < 0.001, respectively). Obesity was strongly associated with both the body mass index (BMI) and the WHR (loading = 0.82, p < 0.001; loading = 0.67, p < 0.001, respectively). WHR served as a moderator; the interaction effect between WHR and IR on the apnoea–hypopnea index (AHI) was significant (coefficient = − 2.451; p = 0.023). Mediation analyses showed that WHR explained 14.93%, 14.02%, and 13.10% of the associations between IR and AHI, the oxygen desaturation index, and the micro-arousal index, respectively. Multifactorial relationships are apparent among IR, WHR, and OSA. The complex interrelationships highlight the intricate clinical interactions among metabolic dysfunction, central obesity, and sleep-disordered breathing, emphasizing the multifaceted nature of OSA and its related health implications.

The association between allergic rhinitis (AR) and behaviour problems (BPs) is still controversy. Furthermore, potential critical mediating role of sleep disturbance (SD) in their association has not been explored. A total of 18,316 children aged 6 to 12 (mean age 7.89 years, male: 53.1%) were recruited from 34 primary schools from Shanghai, China. Demographic information, medical history, Children's Sleep Habits Questionnaire (CSHQ), and Conners' Parent Rating Scale (CPRS) were reported or scored by guardians via online survey. Logistic regression models with adjustment were employed to investigate the association between self-reported AR and BPs. Reproducible mediation analyses were used to explore the mediation effect of SD. The prevalence of AR, SD and any BP was 32.9%, 23.3% and 18.0%, respectively. Adjusted odds ratios (ORs) for BPs were significantly higher in children with AR compared to those without (all p < 0.001): for conduct problems the OR was 1.77 (95% CI 1.54-2.03); learning problems 1.67 (1.48-1.89); psychosomatic problems 1.82 (1.56-2.12); impulsive-hyperactive 1.68 (1.50-1.88); anxiety 1.36 (1.19-1.55); and hyperactivity 1.67 (1.49-1.88). Mediation analysis indicated that SD mediated the association between AR and BPs, with mediation proportions ranging from 32.6% to 64.1% (all p < 0.001), among which daytime sleepiness and sleep disordered breathing contributed most. Children with AR have higher odds of presenting BPs, and SD significantly mediates these associations. These results highlight the importance of proper screening and management of SD and BPs in urban children with AR. registration name (Effect of OSAHS on cognitive behavioural dysfunction in school-aged children: a large-scale prospective cohort study); registration number (ChiCTR1800014488); URL of the registry (https://www.chictr.org.cn/showproj.html?proj=24763).

Intestinal barrier dysfunction and systemic inflammation are common in obstructive sleep apnoea (OSA). We aimed to investigate the role of melatonin, an anti-inflammatory mediator, in mediating the relationships between OSA, intestinal barrier dysfunction and systemic inflammation. Two hundred and thirty-five male participants who complained with sleep problems and underwent whole night polysomnography at our sleep centre between 2017 and 2018 were enrolled. Polysomnographic data, anthropometric measurements and biochemical indicators were collected. Serum melatonin, intestinal barrier function biomarker zonula occludens-1 (ZO-1) and inflammatory biomarkers C-reactive protein (CRP) with lipopolysaccharide (LPS) were detected. Spearman's correlation analysis assessed the correlations between sleep parameters, melatonin and biomarkers (ZO-1, LPS and CRP). Mediation analysis explored the effect of OSA on intestinal barrier dysfunction and systemic inflammation in moderate-severe OSA patients. As OSA severity increased, serum melatonin decreased, whereas ZO-1, LPS and CRP increased. Spearman's correlation analysis showed that serum melatonin was significantly negatively correlated with ZO-1 (r = -0.19, p < .05) and LPS (r = -0.20, p < .05) in the moderate-OSA group; serum melatonin was significantly negatively correlated with ZO-1 (r = -0.46, p < .01), LPS (r = -0.35, p < .01) and CPR (r = -0.30, p < .05) in the severe-OSA group. Mediation analyses showed melatonin explain 36.12% and 35.38% of the effect of apnoea-hypopnea index (AHI) on ZO-1 and LPS in moderate to severe OSA patients. Our study revealed that melatonin may be involved in mediating intestinal barrier dysfunction and systemic inflammation in moderate-to-severe OSA patients.

Dyslipidemia is a hallmark of obstructive sleep apnea (OSA)-induced metabolic syndrome, yet the mechanisms remain poorly understood. We conducted a genome-wide association study on lipid traits in the OSA cohorts, identifying the SNP rs3745683 in ANGPTL8 , significantly associated with reductions in multiple lipid traits. ANGPTL8, an essential lipogenic hormone and potential therapeutic target for metabolic syndrome, showed elevated expression in OSA patients compared to healthy controls, strongly correlated with increased insulin levels. Notably, ANGPTL8 expression can be upregulated by insulin stimulation, indicating it as an insulin-responsive hormone regulating dyslipidemia in OSA. Mechanistically, SNP rs3745683 attenuated ANGPTL8 transcription by inhibiting its binding to transcription factor YBX1. Insulin prompted AKT1 to phosphorylate YBX1 at Ser102, facilitating YBX1’s nuclear translocation and subsequent regulation of ANGPTL8 expression and lipid synthesis. Specific knockdown of YBX1 in mouse liver confirmed its necessity for ANGPTL8 expression and hepatic lipid synthesis in vivo. Our findings highlight ANGPTL8 as a critical regulator of dyslipidemia in OSA patients, offering a promising therapeutic avenue for managing metabolic syndrome in OSA.

Background: The study aimed to explore the relationship between low-density lipoprotein cholesterol (LDL-C) genetic variants and obstructive sleep apnea (OSA) and its complications, including cardiovascular diseases (CVD), insulin resistance (IR), and metabolic syndrome (MS). Method: 4329 individuals with suspected OSA who underwent a comprehensive assessment of anthropometric, biochemical, and polysomnography (PSG) data, along with 30 LDL-C single nucleotide polymorphisms (SNPs) were enrolled. The 10-year Framingham CVD risk score (FRS), IR and MS were evaluated for each subject. Linear regression and logistic regression were utilized to examine the correlations among these variables. Results: After the Benjamini-Hochberg correction, linear regression results indicated positive correlations between variants rs3741297 and rs629301 with FRS (β = 0.031, P_BH=0.002; β = 0.026, P_BH=0.015). Logistic regression revealed that rs3741297 increased MS risk among total subjects [OR = 1.67 (95% CI:1.369–2.038), P_BH=1.32 × 10^− 5] and increased IR risk in females [OR = 3.475 (95% CI:1.653–7.307), P_BH=0.03]. In males, rs2642438 decreased MS risk [OR = 0.81 (95% CI:0.703–0.933), P_BH=0.045]. Conclusions: The rs3741297 variant correlated with susceptibility to CVD, IR, and MS in the OSA population. OSA, CVD, IR and MS share a potentially common genetic background, which may promote precision medicine. Cinical trial registration: The study protocol was registered with the Chinese Clinical Trial Registry (ChiCTR1900025714).

Objectives: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. Methods: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. Results: The SASHB was independently associated with fasting blood glucose (FBG) (β = 0.058, P = 0.016), fasting insulin (FIN) (β = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (β = 0.058, P = 0.011), total cholesterol (TC) (β = 0.100, P < 0.001), total triglycerides (TG) (β = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (β = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (β = 0.051, P = 0.049), apolipoprotein B (apoB) (β = 0.136, P < 0.001), apolipoprotein E (apoE) (β = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. Conclusions: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. Trial registration: ChiCTR1900025714 {http://www.chictr.org.cn/}; Prospectively registered on 6 September 2019; China.