ABSTRACT With ascent to high altitude (HA), increased ventilation reduces the pressure of P a CO 2 (i.e., hypocapnia), resulting in respiratory alkalosis. A subsequent renal compensation is mediated through reductions in [HCO 3 − ] a , partly‐correcting pH a . High inter‐individual variability exists in ventilation, blood oxygenation, and acid–base responses with ascent to HA, but potential sex differences have not been well‐characterized. We recruited 38 lowland participants (20 M; 18 F) before and after rapid ascent to and residence at 3500 m over 10 days in La Paz, Bolivia. We performed radial arterial blood draws to assess blood oxygenation and acid–base variables before (1100 m), and following ascent to 3500 m both early HA (E‐HA; D2/3) and late HA (L‐HA; D9/10). With E‐HA, all participants had higher calculated V̇ A , and lower P a O 2 and S a O 2 ( p < 0.0001), with subsequent increases in A , [Hb] and C a O 2 L‐HA ( p = 0.0056; p = 0.0003; p = 0.0013). Although females had higher A and P a O 2 than males E‐HA ( p < 0.0001; p = 0.0143), males had higher [Hb] and C a O 2 at 1100 m, at both E‐HA ( p = 0.0008; p = 0.0085) and L‐HA ( p = 0.0007; p = 0.0045). E‐HA, all participants had lower P a CO 2 and [HCO 3 − ] a , and higher pH a than 1100 m ( p < 0.0001; p = 0.0004, p < 0.0001), suggesting respiratory alkalosis and partial renal compensation. L‐HA, P a CO 2 and [HCO 3 − ] a were further reduced ( p = 0.0062; p = 0.0202), with pH a only partly‐compensated ( p = 0.4306). E‐HA, P a CO 2 , [HCO 3 − ] a and pH a were significantly lower in females ( p < 0.0001; p < 0.0001; p = 0.0457), suggesting more complete renal compensation. However, these sex‐differences were not apparent at L‐HA ( p > 0.5341). This is the first clear demonstration of differential ventilatory, oxygenation and acid–base compensation between sexes with rapid ascent to HA.
ABSTRACT Objective To assess whether associations between adipose tissue distribution and VMS differ according to menopausal status and to evaluate these associations within the framework of interorgan communication. Methods This study included 408 Polish women aged 40–65 years. Menopausal status was classified according to STRAW+10 criteria. Adiposity distribution was characterized using a combination of anthropometric indicators and multifrequency bioelectrical impedance. Hot flash and night sweat frequency and bothersomeness were classified as low, moderate, or high. Results Postmenopausal women had greater abdominal adiposity and reported more frequent and bothersome VMS than perimenopausal women. Associations between adiposity measures and VMS differed by menopausal status. Among perimenopausal women, greater triceps skinfold thickness was associated with more frequent hot flashes (OR, 1.53; 95% CI, 1.16–2.01), a higher sum of skinfold thicknesses with greater hot flash bothersomeness (OR, 1.36; 95% CI, 1.05–1.76), and higher WHtR with more frequent night sweats (OR, 1.44; 95% CI, 1.10–1.88). In postmenopausal women, greater abdominal skinfold thickness was associated with more frequent hot flashes (OR, 1.78; 95% CI, 1.07–2.95), whereas higher WHR and WHtR were associated with lower odds of VMS. Conclusions Patterns linking regional fat distribution with VMS varied between perimenopausal and postmenopausal women. In perimenopausal women, indicators of greater trunk and abdominal adiposity were associated with a less favorable VMS profile. In postmenopausal women, the direction of associations depended on the adiposity measure examined. These findings are consistent with the hypothesis that adipose tissue may contribute to VMS expression through endocrine, metabolic, and inflammatory processes involved in interorgan communication.
ABSTRACT Neutral sphingomyelinase (nSMase) hydrolyzes sphingomyelin to generate ceramide, a key bioactive lipid implicated in a number of pathological processes, including insulin resistance and diabetes. In this study, we investigate the role and mechanism of nSMase2 signaling in skeletal muscle lipid metabolic disorders and insulin resistance associated with Western diet (WD)‐induced obesity. Six‐week‐old C57BL/6J mice were fed either a WD enriched in saturated fat (46%) and fructose (17.5%) or a standard chow diet (CD) for 16 weeks. GW4869, an nSMase inhibitor, was administered intraperitoneally at a dose of 2.0 μg/g body weight every 48 h for 12 weeks. Sixteen weeks of WD feeding increased plasma nSMase activity and skeletal muscle nSMase2 expression that were associated with reduced insulin metabolic signaling in the phosphoinositide 3‐kinase/protein kinase B pathway, the development of glucose intolerance, and insulin resistance, all of which were blunted by GW4869 treatment. Concurrently, 16 weeks of WD feeding increased ceramide production and skeletal muscle CD36‐mediated signaling, which correlated with excessive lipid droplet accumulation and increased free fatty acid (FFA) levels in skeletal muscle ex vivo. These lipid metabolic disturbances were attenuated, in vivo, by treatment of mice with GW4869. Moreover, GW4869 inhibited WD‐induced pathological changes of skeletal muscle mitochondrial dysfunction, excessive oxidative stress, fibrosis and fiber type transition. These findings demonstrate that nSMase2 is involved in regulating CD36 signaling and may contribute to skeletal muscle FFA uptake, mitochondrial dysfunction, oxidative stress, fibrosis, and associated skeletal muscle insulin resistance in a mouse model of WD‐induced obesity.
ABSTRACT The gut microbiome communicates bidirectionally with the brain and peripheral metabolic organs to regulate appetite and body weight. Semaglutide (SEMA), a GLP‐1 receptor agonist, produces robust weight loss by reducing food intake, largely through brain GLP‐1 receptors, yet whether its effects on the gut microbiome are secondary to this centrally driven hypophagia is poorly understood. Given the profound impact of SEMA on food intake and body weight, we propose that SEMA treatment reshapes gut microbial composition and that these shifts are correlated with metabolic outcomes. Diet‐induced obese rats received a 4‐week SEMA treatment and gut microbial composition was analyzed using 16S rRNA gene sequencing. To differentiate the impact of reduced food intake associated with SEMA from other effects of the drug treatment on the gut microbiome, a pair‐fed to SEMA group was tested. SEMA significantly reduced body weight gain and food intake in both sexes. Significant SEMA‐induced changes in microbial richness and evenness were detected. Linear discriminant analysis Effect Size (LEfSe) identified enrichment of Firmicutes taxa—particularly members of the Clostridiaceae family—in SEMA‐treated rats, whereas controls showed greater representation of Bacteroidota taxa. Sex‐specific associations between host metabolic parameters and gut microbial composition were also identified. These findings demonstrate profound, not necessarily health positive, partly sex‐specific gut microbial community shifts following GLP‐1 analogue treatment. Many of the changes in the gut microbiota were not simply driven by the decreased food intake. Thus, GLP‐1 analogue treatment engages the gut microbiome through both food intake–dependent (brain‐to‐gut) and intake‐independent pathways.
