Hypoxaemia occurs in intermittent forms, such as obstructive sleep apnoea, and in continuous forms, such as at high altitude, and is increasingly recognized as a modulator of cardiometabolic risk. Although hypoxaemia alters postprandial glucose and lipid metabolism, its effects on ketone bodies remain unclear. Using a randomized crossover design, we examined whether 6 h of normoxaemia or intermittent hypoxaemia (15 hypoxaemic cycles/h targeting ∼85% peripheral oxyhaemoglobin saturation with 100% medical-grade nitrogen) alters plasma β-hydroxybutyrate (BHB) concentrations in 12 young adult females (mean [SD]: 21 [3] years) following a high-fat meal (33% of estimated daily energy requirements; 59% of energy from fat). In a follow-up session, a subset (n = 8) completed 6 h of continuous hypoxaemia (fraction of inspired oxygen ∼12.0% in a normobaric chamber). Postprandial data were analysed using baseline-adjusted linear mixed-effects models, with Bonferroni post hoc tests. A time × condition interaction (P = 0.010) indicated that BHB concentrations at 360 min were higher during continuous hypoxaemia (0.247 mmol/L; 95% CI: 0.218-0.275) than normoxaemia (0.176 mmol/L; 95% CI: 0.153-0.200; PBonferroni = 0.029) and intermittent hypoxaemia (0.163 mmol/L; 95% CI: 0.139-0.186; PBonferroni = 0.002), representing increases of 13.0% and 14.2% in estimated marginal means, respectively. This response was accompanied by higher postprandial plasma glucose and triglyceride concentrations during continuous hypoxaemia than during normoxaemia and intermittent hypoxaemia (PBonferroni ≤ 0.002), despite similar plasma insulin and non-esterified fatty acid responses across conditions (P ≥ 0.081). These findings indicate that continuous hypoxaemia increases late postprandial plasma BHB concentrations in young adult females.

Abstract Hypoxemia occurs in intermittent forms, such as obstructive sleep apnea, and in continuous forms, such as at high altitude, and is increasingly recognized as a modulator of cardiometabolic risk. Although hypoxemia alters postprandial glucose and lipid metabolism, its effects on ketone bodies remain unclear. Using a randomized crossover design, we examined whether six hours of normoxemia or intermittent hypoxemia (15 hypoxemic cycles/hour targeting ∼85% peripheral oxyhemoglobin saturation with 100% medical-grade nitrogen) alters plasma β-hydroxybutyrate (BHB) concentrations in 12 young adult females (mean [SD]: 21 [3] years) following a high-fat meal (33% of estimated daily energy requirements; 59% of calories from fat). In a follow-up session, a subset (n = 8) completed six hours of continuous hypoxemia (fraction of inspired oxygen ∼12.0% in a normobaric chamber). Postprandial data were analyzed using baseline-adjusted linear mixed-effects models, with Bonferroni post hoc tests. A time × condition interaction (P = 0.010) indicated that BHB concentrations at 360 minutes were higher during continuous hypoxemia (0.247 mmol/L; 95% CI: 0.218-0.275) than normoxemia (0.176 mmol/L; 95% CI: 0.153-0.200; P Bonferroni = 0.029) and intermittent hypoxemia (0.163 mmol/L; 95% CI: 0.139-0.186; P Bonferroni = 0.002), representing increases of 13.0% and 14.2% in estimated marginal means, respectively. This response was accompanied by higher postprandial plasma glucose and triglyceride concentrations during continuous hypoxemia than during normoxemia and intermittent hypoxemia (P Bonferroni ≤ 0.002), despite similar plasma insulin and non-esterified fatty acid responses across conditions (P ≥ 0.081). These findings indicate that continuous hypoxemia increases late postprandial plasma BHB concentrations in young adult females. New Findings What is the central question of this study? What are the effects of normoxemia, intermittent hypoxemia, and continuous hypoxemia on plasma β-hydroxybutyrate (BHB) concentrations in young adult females after a high-fat meal? What is the main finding and its importance? Compared to normoxemia, young adult females showed higher postprandial plasma BHB concentrations during continuous hypoxemia, but not during intermittent hypoxemia, despite similar changes in plasma concentrations of two main regulators of BHB production (non-esterified fatty acids and insulin) across experimental conditions. These findings suggest that continuous hypoxemia modifies postprandial BHB concentrations through mechanisms not fully explained by circulating non-esterified fatty acids or insulin concentrations alone.

Introduction: Menstrual cycle phase has been proposed as a source of intra-individual variability in resting energy expenditure and the thermic effect of food in premenopausal females, yet studies examining the thermic effect of food across menstrual cycle phases report conflicting findings. Methods: This protocol describes a secondary analysis of prespecified outcomes from a non-randomized, two-period crossover trial primarily designed to assess postprandial plasma triglyceride concentrations across menstrual cycle phases (ClinicalTrials.gov: NCT07459465 ) in 12 premenopausal females aged 18-30 years, free of chronic disease and hormonal contraceptive use, recruited in Ottawa, Canada. Participants complete two experimental sessions: one in the early follicular phase and one in the mid-luteal phase, each involving consumption of a high-fat meal. Eleven secondary outcomes will be reported: fasting resting energy expenditure, thermic effect of food, respiratory exchange ratio, carbohydrate oxidation rate, lipid oxidation rate, desire to eat, hunger, fullness, prospective food consumption, serum beta-estradiol, and serum progesterone. Masked outcome analyses will be performed using linear mixed-effects models. Results: Recruitment began on 26 March 2026; results will be reported in the Stage 2 manuscript. Discussion: Findings from this trial may help clarify whether menstrual cycle phase constitutes a meaningful source of intra-individual variability in energy metabolism, with implications for the design of metabolic research in premenopausal females.

Exposure to reduced oxygen levels occurs in several real-world contexts, such as during air travel or altitude exposure, and emerging evidence suggests that hypoxia may interact with molecular pathways involved in circadian regulation. This exploratory study investigated the effects of normobaric hypoxia on circadian phase shifting in humans, compared to luminotherapy combined with exogenous melatonin. Using a randomised crossover design, 11 healthy adults (6 men, 5 women; mean age 23.3 ± 1.9 years) completed one baseline and two 48-h experimental conditions. The baseline established individual circadian markers. Both experimental conditions simulated a 4-h phase advance. In the hypoxia condition, participants were exposed to reduced oxygen levels (inspired oxygen fraction of 12%) for 2 h, beginning 2 h after habitual wake time. In the luminotherapy and melatonin condition, participants received three-hour morning light therapy (500 nm, 506 lx) at the same time point, combined with 5 mg melatonin administered 6 h before bedtime. Salivary melatonin was collected across conditions to determine dim-light melatonin onset (DLMO). Both conditions produced earlier melatonin onset compared to baseline. The luminotherapy and melatonin condition resulted in a significant phase advance of approximately 78 min. The hypoxia condition produced an average phase advance of approximately 35 min, which was not statistically significant. The present findings do not allow us to determine whether hypoxia can induce circadian phase shifts, while light and melatonin remain an effective intervention. Further research is needed to clarify mechanisms and evaluate hypoxia as a tool for circadian modulation.

This narrative review explores the intricate relationship between biological rhythms and the natural cycles of light and darkness, known as circadian rhythms. This review begins with an examination of empirical evidence dating back to 1729, which indicates that a particular plant displayed rhythmic behavior even in complete darkness. It then considers the evolution and significance of internal biological clocks in humans. The pivotal role of circadian rhythms in regulating physiological processes (e.g., sleep-wake cycles, body temperature, and hormone levels) emphasizing their influence on overall health and wellbeing is discussed. This review also highlights the critical importance of maintaining circadian timing alignment with the environment, as desynchronization can lead to a range of adverse outcomes, including cardiovascular, metabolic, and psychological disorders. By integrating the genetic, physiological, and behavioral mechanisms underlying and associated with biological clocks and rhythms in humans, this review aims to provide clinicians and researchers with a comprehensive perspective on the holistic nature of biological rhythms and their implications for health. Furthermore, the concepts associated with Chrono-intervention, such as chrononutrition and chronomedicine, are introduced as promising approaches to optimizing health outcomes by aligning interventions with the body's natural rhythms are introduced. Through this consideration, this review seeks to contribute to a deeper understanding of chronobiology and its potential applications in improving human health and performance.

Introduction Circadian desynchronization, evident in scenarios such as jet lag, shift work, and circadian rhythm sleep disorders, detrimentally affects sleep quality and overall health, both acutely and chronically. Aligning the circadian system with environmental time cues is therefore essential for maintaining physiological and psychological well-being. While luminotherapy and melatonin supplementation are widely used to facilitate circadian realignment, emerging evidence suggests that fluctuations in oxygen levels may also help in circadian realignment. However, the effect of hypoxia on the synchronisation of the circadian clock in humans remains largely unexplored. Methods Using a randomized controlled crossover study design, 11 healthy participants (6 men, 5 women, mean age 23.3 ± 1.9 years) completed one baseline condition and two 48-h experimental conditions. The baseline condition (BL) was used to establish circadian markers. Both experimental conditions simulated a phase advance of 4 hours. In condition 1 (Hypo), participants underwent a 2-hour normobaric hypoxic exposure (FiO2 = 12%), starting 2 h after habitual wake time. In condition 2 (Lum+Mel), participants received a 3-hour luminotherapy session (500 nm, 506 lux) at the same time point, combined with 5 mg of exogenous melatonin administered 6 hours before usual bedtime. Salivary melatonin levels were measured in each phase of the study to assess circadian phase shifts. Data were analyzed using linear mixed models. Results Salivary melatonin levels increased progressively over time in all conditions (p < 0.001), with significant differences observed between experimental conditions (p < 0.001), but no interaction effect (p = 0.854). Exposure to hypoxia significantly reduced oxyhemoglobin saturation (p < 0.05) and increased heart rate and subjective symptoms of fatigue. In terms of circadian phase, the dim light melatonin onset (DLMO) occurred 1.30 hour (78 minutes) earlier in the Lum+Mel condition compared to baseline (p=0.001). In the hypoxia condition, the DLMO occurred on average 0.58 hour (34.8 minutes) earlier than baseline, but this change did not reach statistical significance (p=0.156). Conclusions This study provides preliminary evidence that normobaric hypoxia may modestly advance the human circadian phase, although not to a statistically significant extent. In contrast, combined phototherapy and melatonin administration produced a robust and significant phase advance in salivary melatonin onset. These findings suggest that while hypoxia may influence circadian timing, established interventions like light and melatonin remain more effective for circadian realignment. Further research is warranted to elucidate the mechanisms and optimize the application of hypoxia in circadian modulation. ### Competing Interest Statement The authors have declared no competing interest. Institut du Savoir Montfort, 2016-018-Chair-PIMB Natural Sciences and Engineering Research Council, RGPIN-2019- 792 04438

Hypoxemia occurs during exposure to high altitude (continuous hypoxemia) or in the context of breathing disorders such as obstructive sleep apnea (OSA; intermittent hypoxemia). Growing evidence demonstrates that hypoxemia induces an anorexigenic effect on appetite; however, few studies have assessed hypoxemia-related reductions in appetite during acute passive exposures and during intermittent hypoxemia. This study thus pooled together four same-single-site randomized crossover trials using simulated models of high altitude (fraction of inspired oxygen = 0.1200, ∼5000 meters) and moderate OSA (∼15 hypoxemic cycles per hour, ∼85 oxyhemoglobin saturation). Changes in appetite were evaluated during six hours of passive normoxia and intermittent or continuous hypoxemia in postprandial or fasting states among healthy young adults (n = 40) and middle-aged individuals living with OSA (n = 7). Our results demonstrate that (1) acute passive intermittent hypoxemia leads to statistically significant, but likely not clinically significant reductions in appetite in the postprandial state, (2) the anorexigenic effect of acute passive hypoxemia on appetite is not consistent across hypoxemic methods and nutritional states, and (3) variations in individual factors may influence appetite responses during normoxia and hypoxemia. These findings indicate that the effect of acute passive hypoxemia on appetite is heterogeneous, particularly across different hypoxemic methods and nutritional states.

Obstructive sleep apnoea is characterized by chronic intermittent hypoxaemia and is independently associated with an increased risk of metabolic comorbidities (e.g. type II diabetes and ischaemic heart disease). These comorbidities could be attributable to hypoxaemia-induced alterations in blood lipid profiles. However, it remains unclear whether intermittent hypoxaemia alters triglyceridaemia differently between biological sexes. Therefore, we used a randomized crossover design to examine whether 6 h of moderate intermittent hypoxaemia (15 hypoxaemic cycles/h, 85% oxyhaemoglobin saturation) alters plasma triglyceride levels differently between men and women after a high-fat meal. Relative to men, women displayed lower levels of total triglycerides, in addition to denser triglyceride-rich lipoprotein triglycerides (TRL-TG; mainly very low-density lipoprotein triglycerides and chylomicron remnant triglycerides) and buoyant TRL-TG (mainly chylomicron triglycerides) during normoxia (ambient air) and intermittent hypoxaemia (sex x time: all P <= 0.008). Intermittent hypoxaemia led to higher triglyceride levels (condition: all P <= 0.016); however, this effect was observed only in men (sex x condition: all P <= 0.002). Compared with normoxia, glucose levels were higher in men and lower in women during intermittent hypoxaemia (sex x condition: P < 0.001). The different postprandial responses between biological sexes occurred despite similar reductions in mean oxyhaemoglobin saturation and similar elevations in insulin levels, non-esterified fatty acid levels and mean heart rate (sex x condition: all P >= 0.185). These results support growing evidence showing that intermittent hypoxaemia impacts men and women differently, and they might help to explain biological sex-related discrepancies in the rate of certain comorbidities associated with intermittent hypoxaemia.

AbstractObstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxemia, which is associated with progressive loss of kidney function, where postprandial fluctuations in renal physiology may further compromise oxygen supply and kidney function. Therefore, we measured biomarkers of acute kidney injury (AKI) following a high‐fat meal with and without intermittent hypoxemia. Eighteen healthy young men (mean age [SD]: 22.7 years [3.1]) and seven middle‐aged to older individuals with OSA (54.4 years [6.4]) consumed a high‐fat meal during normoxia or intermittent hypoxemia (~15 hypoxic cycles per hour, ~85% oxyhemoglobin saturation) for 6 h. We observed no changes in estimated glomerular filtration rate and plasma concentrations of creatinine, neutrophil gelatinase‐associated lipocalin (NGAL), and kidney injury molecule‐1 (KIM‐1) at any measured time points. In both groups, plasma concentrations of interleukin‐18 (IL‐18) increased after 6 h during normoxia only (p = 0.033, ηp2 = 0.122), and plasma concentrations of liver‐type fatty acid‐binding protein (L‐FABP) transiently decreased after 3 h in both conditions (p = 0.008, ηp2 = 0.152). These findings indicate that AKI biomarkers are not acutely elevated during the postprandial state with or without intermittent hypoxemia, suggesting that other mechanisms may play more important roles in the progression of kidney disease in OSA.

Persistent organic pollutants (POPs) accumulation and hypoxia are two factors proposed to adversely alter adipose tissue (AT) functions in the context of excess adiposity. Studies have shown that preadipocytes exposure to dioxin and dioxin-like POPs have the greatest deleterious impact on rodent and immortalized human preadipocyte differentiation, but evidence on human preadipocytes is lacking. Additionally, hypoxia is known to strongly interfere with the dioxin-response pathway. Therefore, we tested the effects of pre-differentiation polychlorinated biphenyl (PCB)126 exposure at 10 µM for 3 days and subsequent differentiation under hypoxia on human subcutaneous adipocytes (hSA) differentiation, glucose uptake and expression of selected metabolism- and inflammation-related genes. Pre-differentiation PCB126 exposure lowered the adenosine triphosphate (ATP) content, glucose uptake and leptin expression of mature adipocytes but had limited effects on differentiation under normoxia (21% O2). Under hypoxia (3% O2), preadipocytes ability to differentiate was significantly reduced as reflected by significant decreased lipid accumulation and downregulation of key adipocyte genes such as peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin. Hypoxia increased glucose uptake and glucose transporter 1 (GLUT1) expression but abolished the adipocytes insulin response and GLUT4 expression. The expression of pro-inflammatory adipokine interleukin-6 (IL-6) was slightly increased by both PCB126 and hypoxia, while IL-8 expression was significantly increased only following the PCB126-hypoxia sequence. These observations suggest that PCB126 does not affect human preadipocyte differentiation, but does affect the subsequent adipocytes population, as reflected by lower ATP levels and absolute glucose uptake. On the other hand, PCB126 and hypoxia exert additive effects on AT inflammation, an important player in the development of chronic diseases such as type 2 diabetes and cardiovascular diseases.

Abstract Introduction Because of their double reality of university student and athlete, varsity athletes are particularly at risk of having sleep difficulties, but also depression and anxiety symptoms. To this day, there is almost no data available characterizing the sleep of Canadian varsity student-athletes, while these athletes must often combine their studies and sports practice with a job to support themselves. As part of a larger study, the aim of the present study was to investigate the relationship between sleep and well-being in young Canadian varsity athletes at the beginning of their sports season. Methods A team of 16 Canadian varsity basketball players that will undergo a sleep management program completed a modified version of the Pittsburgh Sleep Index Quality (PSQI), the insomnia severity index (ISI), the Epworth Sleepiness Scale (ESS), the Generalized Anxiety Disorder-7 (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), and the Athlete Burnout Questionnaire (ABQ) before the intervention at the start of the season. The relationships between scores on each well-being questionnaire and scores on the sleep questionnaires were investigated using Pearson product moment correlations. Results Total GAD-7 scores were significantly associated with PSQI scores (r=.666, p=.005) and ISI scores (r=.755, p Conclusion These preliminary results suggest that sleep disturbances, such as insomnia symptoms and poor sleep quality are closely associated with anxiety, depression, and athlete burnout symptoms in varsity athletes. Future analyses of this study will allow us to verify whether participation in a program aimed at improving sleep can have an impact on their mental health, as well as on other aspects related to the practice of their sport. Support (if any)

There has been much consideration over whether exogenous ketone bodies have the capacity to enhance exercise performance through mechanisms such as altered substrate metabolism, accelerated recovery, or neurocognitive improvements. This systematic review aimed to determine the effects of both ketone precursors and monoesters on endurance exercise performance. A systematic search was conducted in PubMed, SPORTDiscus, and CINAHL for randomized controlled trials investigating endurance performance outcomes in response to ingestion of a ketone supplement compared to a nutritive or nonnutritive control in humans. A meta-analysis was performed to determine the standardized mean difference between interventions using a random-effects model. Hedge's g and 95% confidence intervals (CI) were reported. The search yielded 569 articles, of which eight were included in this review (80 participants; 77 men and three women). When comparing endurance performance among all studies, no significant differences were found between ketone and control trials (Hedges g = 0.136; 95% CI [-0.195, 0.467]; p = .419). Subanalyses based on type of endurance tests showed no significant differences in time to exhaustion (Hedge's g = -0.002; 95% CI [-0.312, 0.308]; p = .989) or time trial (Hedge's g = 0.057; 95% CI [-0.282, 0.395]; p = .744) values. Based on these findings, exogenous ketone precursors and monoesters do not exert significant improvements on endurance exercise performance. While all studies reported an increase in blood ketone concentrations after ingestion, ketone monoesters appear to be more effective at raising concentrations than precursors.

Introduction: Acute hypoxia is known to increase circulating nonesterified fatty acid (NEFA) levels. Adipose tissue lipolysis is a major source of NEFA into circulation and insulin suppresses this process when the tissue is insulin sensitive. NEFA can be esterified to triglycerides and/or completely/partially oxidized, the latter leading to ketogenesis in the liver. To our knowledge, the effect of hypoxia on ketogenesis, more specifically ß-hydroxybutyrate (ßOHB) levels, remains unknown in humans. Therefore, the objective of this study was to determine the effect of acute intermittent and continuous hypoxia on circulating ßOHB levels under different feeding status. Methods: Plasma samples from three different randomized crossover studies were assessed for ßOHB concentrations. In the first study, 14 healthy men (23 ± 3.5 years) were exposed to 6 h of normoxia or intermittent hypoxia (IH-Fed) (15 hypoxic events/hour) following an isocaloric meal. In the second study, 10 healthy men (26 ± 5.6 years) were exposed to 6 h of continuous normobaric hypoxia (CH-Fasted) (FiO2 = 0.12) or normoxia in the fasting state. In the third study (CH-Fed), 9 healthy men (24 ± 4.5 years) were exposed to 6 h of normoxia or CH in a constant prandial state. ßOHB, NEFA and insulin levels were measured during all sessions. Results: In the IH-Fed study, ßOHB and NEFA levels tended to be greater over 6 h of IH (condition × time interaction, ßOHB p = 0.108 and NEFA p = 0.062) compared to normoxia. In the CH-Fasted study, ßOHB and NEFA levels increased over time in both experimental conditions, this effect being greater under CH (condition × time interaction, ßOHB p = 0.070; NEFA p = 0.046). In the CH-Fed study, ßOHB levels slightly increased up to 180 min before falling back to initial concentrations by the end of the protocol in both normoxia and CH (main effect of time, p = 0.062), while NEFA were significantly higher under CH (p = 0.006). Conclusion: Acute normobaric hypoxia exposure tends to increase plasma ßOHB concentrations over time in healthy men. The stimulating effect of hypoxia on plasma ßOHB levels is however attenuated during postprandial and prandial states.

It is increasingly recognized that hypoxia may develop in adipose tissue as its mass expands. Adipose tissue is also the main reservoir of lipophilic pollutants, including polychlorinated biphenyls (PCBs). Both hypoxia and PCBs have been shown to alter adipose tissue functions. The signaling pathways induced by hypoxia and pollutants may crosstalk, as they share a common transcription factor: aryl hydrocarbon receptor nuclear translocator (ARNT). Whether hypoxia and PCBs crosstalk and affect adipokine secretion in human adipocytes remains to be explored. Using primary human adipocytes acutely co-exposed to different levels of hypoxia (24 h) and PCB126 (48 h), we observed that hypoxia significantly inhibits the PCB126 induction of cytochrome P450 (CYP1A1) transcription in a dose-response manner, and that Acriflavine (ACF)-an HIF1α inhibitor-partially restores the PCB126 induction of CYP1A1 under hypoxia. On the other hand, exposure to PCB126 did not affect the transcription of the vascular endothelial growth factor-A (VEGFA) under hypoxia. Exposure to hypoxia increased leptin and interleukin-6 (IL-6), and decreased adiponectin levels dose-dependently, while PCB126 increased IL-6 and IL-8 secretion in a dose-dependent manner. Co-exposure to PCB126 and hypoxia did not alter the adipokine secretion pattern observed under hypoxia and PCB126 exposure alone. In conclusion, our results indicate that (1) hypoxia inhibits PCB126-induced CYP1A1 expression at least partly through ARNT-dependent means, suggesting that hypoxia could affect PCB metabolism and toxicity in adipose tissue, and (2) hypoxia and PCB126 affect leptin, adiponectin, IL-6 and IL-8 secretion differently, with no apparent crosstalk between the two factors.