American journal of physiology. Regulatory, integrative and comparative physiology最新文献

Maternal obesity increases the risk of preterm delivery and rapid transition of offspring from a hypoxemic environment to a normal or elevated oxygen environment, especially if the baby receives oxygen therapy. Maternal obesity may also increase offspring risk of developing hypertension. Thus, we examined whether neonatal hyperoxia (HO) leads to elevated blood pressure (BP) in offspring from lean mothers and exacerbates adverse impact of maternal obesity on offspring BP regulation. Male and female Sprague-Dawley offspring from lean and high-fat diet-fed obese mothers (n = 12-18 mothers/group) were exposed to room air (∼21% O₂) or HO (80% O₂) between postnatal days P3 and P10 and then returned to room air. At 12 wk of age, offspring were instrumented with telemetry probes to measure BP and heart rate (HR). Contrary to our hypothesis, neonatal HO was associated with lower BP compared with control offspring from lean mothers (males: 105 ± 1 vs. 111 ± 1 mmHg; females: 102 ± 0.4 vs. 108 ± 0.4 mmHg) and also reduced BP and HR in hypertensive obese offspring from obese mothers (males: 117 ± 1 vs. 123 ± 1 mmHg and 351 ± 4 vs. 358 ± 5 beats/min; females: 113 ± 1 vs. 116 ± 1 mmHg and 376 ± 2 vs. 390 ± 4 beats/min). In lean offspring from lean mothers, neonatal HO was associated with reduced +dP/dt_max, whereas in obese offspring from obese mothers, HO attenuated cardiac dysfunction when compared with obese offspring not submitted to HO. These results suggest that exposure to HO in early postnatal life is not associated with elevated BP in early adulthood and it does not exacerbate the hypertensive effects of maternal obesity on offspring BP regulation.NEW & NOTEWORTHY Maternal obesity increases risk for preterm birth and neonatal oxygen exposure. We tested whether hyperoxia (80% O₂, P3-P10) worsens maternal obesity-induced hypertension. At 14 wk, BP measured by telemetry showed that hyperoxia unexpectedly lowered BP in lean and obese offspring and attenuated cardiac dysfunction in obese offspring. These findings indicate that neonatal hyperoxia does not exacerbate maternal obesity-induced hypertension and may mitigate early cardiac dysfunction.

Nitrogen dioxide (NO²) is an environmental air pollutant and a potent oxidant Epidemiological studies have revealed a close association between chronic cough and long-term inhalation exposure to NO². ATP can be released from airway/lung epithelial cells upon inhalation exposure to oxidants, and convincing evidence established in recent clinical studies indicating that extracellular ATP in the respiratory tract plays an important role in the pathogenesis of refractory chronic cough. However, whether inhalation exposure to NO² elevates the ATP release in the lung is not yet known. Results of this study showed: 1) In awake rats, acute and chronic inhalation exposures to NO² (5-10 ppm) evoked an increase in the ATP release in the bronchoalveolar lavage fluid (BALF), reaching > 225% of that in the control (room air) group. 2) The NO²- induced increase in ATP release in the lung generated by chronic exposure was substantially greater than that by acute exposure to the same concentration of NO². 3) Chronic but not acute exposure to NO² induced a mild and transient airway inflammation. 4) The elevated ATP release in the lung returned to control within 1-2 days after the acute exposure to NO²; in sharp contrast, the increase in ATP in BALF persisted for < 11-15 days following the chronic exposure when the airway inflammation had already completely recovered. These results suggest that the sustained elevation of ATP release in the lung may act as a contributing factor to the pathogenesis of chronic cough associated with long-term inhalation exposure to NO² in humans.

In many species, the reproductive behavior of females is more sensitive than that of males to energetic challenges, but the physical location of this sex difference is not completely understood. Progress has been facilitated by using Drosophila melanogaster, a genetically tractable species in which reproductive success is closely linked to energetics, and in which only females significantly decrease copulation rate after 48 h of food deprivation (FD). To examine the locus of the sex difference, we masculinized cells of either the nervous system (NS) or the fat body, an analog of the mammalian liver, using transcription inhibition of the sex determination co-factor, transformer-2 (tra2). In genetic (XX) females with a masculinized NS, courtship behavior was masculinized so that they showed robust courtship toward other females, and yet, the response to FD was not masculinized (FD XX females with a masculinized NS and FD female controls both courted and copulated significantly less than their fed counterparts). Thus, a masculinized NS circuit that engages male-typical courtship behavior toward other females is not sufficient to create the male-typical low sensitivity to food deprivation. By contrast, in genetic XX females with a masculinized fat body, the reproductive response to FD was masculinized, perhaps increasing peripheral fuel availability to the brain. These results are consistent with the existence of an evolutionarily conserved mechanism whereby sex determining genes either masculinize or feminize the peripheral organs, such as the fat body, so that males and females employ a different reproductive strategy in habitats where food availability fluctuates.

The ability to withstand low and fluctuating oxygen levels is important for adipose tissue function. Hypoxia in mammalian cells typically stabilizes hypoxia inducible factor (HIF-1α) that alters downstream structural and metabolic pathways, which can have pathological consequences in humans and rodents. Gray seals (Halichoerus grypus) have extensive subcutaneous adipose as blubber, which naturally undergoes oxygen restriction acutely during diving and chronically during fattening. This study explored how blubber regulates responses to chemically induced pseudohypoxia. We obtained blubber biopsies from weaned pups (n = 6) and prepared explants that we incubated with or without cobalt chloride (CoCl₂), which stabilizes HIF-1α under normoxia. One explant per animal was immediately snap-frozen, and the remaining explants and media were collected every 2h. HIF-1α protein accumulation occurred rapidly in both control and CoCl₂-treated explants, peaking at 4h and 2h, respectively. HIF-1α mRNA increased in all explants. Mitochondrial complex I abundance increased in controls. CoCl₂ drove an additional increase in complex I, II and V proteins compared to controls at all time points. Surprisingly, Adiponectin and Ppar-γ were not downregulated. Collagen VI abundance increased 6h after treatment. Our results suggest that blubber explants experience hypoxia in culture, which is enhanced by chemical pseudohypoxia: CoCl₂ produced an additional impact on mitochondrial complex proteins. HIF-1α elevation in response to hypoxic challenge occurred earlier, to a greater extent but was shorter-lived than in other mammalian adipose. Our findings highlight potential differences in responses of seal blubber to hypoxia compared to human and rodent adipose.

Neurons in the nucleus of the solitary tract (NTS) are activated by inputs from the vagus nerve, including those from the gastrointestinal tract. This activation is relayed to CNS regions critical for the control of food intake. Changes to NTS neuron activation therefore impact the transmission of vagal information to the brain. Injection of neuropeptide Y (NPY) and the Y2 receptor agonist PYY-(3-36) into the dorsal vagal complex (DVC) containing the NTS increases food intake. However, how NPY produces this effect is not known. Here we use transgenic mice with EGFP expression driven by the tyrosine hydroxylase promoter (TH-EGFP) to identify NTS catecholamine neurons, as NPY terminals have been found in close proximity to NTS-TH neurons. We recorded from NTS TH-EGFP neurons in horizontal brain slices containing vagal afferents within the solitary tract (ST) using whole-cell patch-clamp techniques. NPY inhibited ST-evoked excitatory post synaptic currents (ST-EPSCs) in approximately two-thirds of TH-EGFP neurons. This effect was blocked by the Y2 receptor antagonist BIIE 0246 and mimicked by the Y2 agonist PYY-(3-36). In contrast, the Y1 receptor agonist L-P-NPY did not inhibit ST-EPSCs. NPY also reduced both basal and vagal-evoked action potentials in CA neurons. Finally, NPY attenuated the ability of the satiety peptide cholecystokinin (CCK) to increase glutamate release onto TH-EGFP neurons, an effect mimicked by PYY-(3-36). These results indicate that NPY inhibits both vagal- and CCK-induced activation of most NTS-TH neurons and suggest a potential mechanism for its effects to increase food intake at the level of the hindbrain.

This essay examines, in an evolutionary perspective, body systems outside the brain that use the catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) as chemical messengers. Peripheral catecholamine systems represent three mechanisms by which the brain regulates the functions of body organs. DA serves as an autocrine-paracrine factor in the kidneys and splanchnic organs, NE is the neurotransmitter of the sympathetic noradrenergic system (SNS), and EPI is the main hormone secreted by adrenomedullary chromaffin cells. Comparative physiological data suggest that the DA autocrine-paracrine system emerged first, followed by noradrenergic nerve networks culminating in the SNS, with the hormonal sympathetic adrenergic system (SAS) appearing most recently. Examples are presented of the diverse ways these catecholamines have been used during evolution, although the ecological niches that conferred selective advantages remain uncertain. The discussion addresses catecholamine receptors, cotransmission, and interactions between catecholaminergic, neuroendocrine, and immune systems. In humans, the transition to bipedalism likely promoted SNS adaptations for orthostatic regulation of brain blood flow as well as for sodium homeostasis and temperature control. The roles of the SAS in organism-wide stress responses, distress, and sympathoadrenal imbalance in fainting are also considered. Concepts such as antagonistic pleiotropy, allostatic load, and autotoxicity are discussed in relation to aging-associated diseases that feature catecholaminergic neurodegeneration. Understanding the phylogeny of peripheral catecholamine systems may provide a foundation for Darwinian medicine.

Allostatic load, a maladaptive biological process wherein physiological stability ("allostasis") fails owing to chronic stress exposure, is traditionally measured by the allostatic load index (ALI). Whether ALI is associated with wearable-assessed physiological responses remains unknown. We aimed to determine the association between ALI and wearable-assessed physiological responses during a 10-wk military training course. Twenty-five participants (12 women) with ALI and suitable wearable data [84.31% complete data (range: 64.71%-97.56%)] were included. ALI (0-8) was calculated using biomarker components from neuroendocrine, autonomic, and immune systems. Device variables included total energy expenditure (TEE), energy expenditure during physical activity (PAEE), daytime heart rate (HR), sleeping HR, nonlinear HR variability (detrended fluctuation analysis, DFA-α₁), and sleep architecture. Flux was calculated as raw (Δ) or absolute difference (|Δ|) in average values between days and nights. Generalized linear mixed effect models assessed the association between high allostatic load (ALI > 4) and responses (α = 0.05). Twelve (4 women) participants experienced ALI > 4. High allostatic load was associated with TEE (β = 0.658, standard error (SE) = 0.002, odds ratio (OR) = 1.931, P < 0.001), Δ in relative PAEE (β = 0.472, SE = 0.002, OR = 1.602, P < 0.001), daytime HR (β = 0.189, SE = 0.002, OR = 1.208, P < 0.001), |Δ| in relative daytime HR (β = 0.262, SE = 0.001, OR = 1.298, P < 0.001), and |Δ| in relative sleeping HR (β = -0.048, SE = 0.001, OR = 0.953, P < 0.001). Every one-standard-deviation increase in absolute TEE, flux in relative PAEE, daytime HR, flux in daytime HR, and reduced flux in sleeping HR increased the risk of high allostatic load by 5%-90%. Chronically elevated and variable cardiometabolic activity with blunted night-to-night variation in sleeping HR may be a digital phenotype of high allostatic load in military personnel.NEW & NOTEWORTHY This investigation for the first time observed an association between the traditional measurement of allostatic load, the allostatic load index, and wearable-assessed physiological responses to strenuous military training stress. We found a novel digital phenotype of allostatic load characterized by chronically elevated and variable cardiometabolic activity with blunted variation in heart rate during sleep. This phenotype may serve as an at-risk profile of high allostatic load and prompt in-training modifications to enhance posttraining readiness.

A rapid change in arterial CO₂ tension causes changes in ventilation, referred to as peripheral hypercapnic chemosensitivity (PHC). The PHC increases from rest to low-intensity exercise yet is not further augmented at higher exercise intensities, where additional ventilatory stimulants are present. During supra-respiratory compensation point (RCP) exercise, as arterial CO₂ tension falls, so does PHC, which may mask the effect of other ventilatory stimuli. Twenty healthy subjects (n = 10 females) completed a maximal exercise test and on subsequent days (days 2 and 3) had PHC measured at rest, 40% of maximal work rate (Wmax), and supra-RCP exercise intensities. On one experimental day, participants were kept isocapnic, and on the other, end-tidal carbon dioxide ([Formula: see text]) declined naturally during supra-RCP exercise (poikilocapnia). PHC was measured as the quotient between the change in ventilation and [Formula: see text] after two breaths of hypercapnic (10% CO₂) gas delivered 3-5 times during each condition. There was a significant increase in PHC during supra-RCP intensities with isocapnia, compared with poikilocapnic exercise (+11.2 ± 6%) (P = 0.0015). Yet during the isocapnia day, there was still no significant increase in PHC from 40% intensity to supra-RCP (P = 0.96). A repeated-measures correlation demonstrated a significant relationship between PHC and [Formula: see text] during poikilocapnia (r = 0.49, P < 0.001), with no significant relationship during isocapnia (r = 0.06, P = 0.57). We conclude that the metabolic milieu associated with supra-RCP exercise does not impact PHC and there is a CO₂-dependent relationship in which [Formula: see text] influences PHC independent of the initial exercise sensitization.NEW & NOTEWORTHY Maintaining end-tidal carbon dioxide ([Formula: see text]) at isocapnic levels during supra-respiratory compensation point (RCP) exercise significantly increased the peripheral hypercapnic chemoresponse (PHC) compared with poikilocapnic conditions. However, neither the isocapnic nor poikilocapnic exercise above RCP resulted in a significant increase in PHC compared with lower intensity exercise. Thus, although prestimulus [Formula: see text] impacts the PHC, supra-RCP exercise does not further augment the PHC beyond low intensity exercise.

Defective postprandial glucagon suppression contributes to chronic hyperglycemia in type 2 diabetes. Although insulin action and secretion have been extensively and quantitatively studied in the literature, less effort has been made to quantify the glucagon stimulatory effect on endogenous glucose production (EGP). This study aims to model the glucagon effect on EGP in healthy humans, capturing the decline of its action following sustained hyperglucagonemia. We analyzed data from 54 nondiabetic individuals studied on two occasions, where they received a glucose, labeled with [3-³H]-glucose, and an insulin infusion, mimicking systemic appearance after an oral glucose challenge, whereas endogenous hormone secretion was suppressed by somatostatin. Glucagon was infused at a rate of 0.65 ng/kg/min starting at 0 min (nonsuppressed occasion) or 120 min to mimic postprandial glucagon suppression (suppressed occasion). Plasma glucose, insulin, and glucagon concentrations were frequently measured for 300 min, and model-independent estimates of EGP were obtained from tracer specific activity. Several physiological models describing the EGP time course as a function of plasma glucose, insulin, and glucagon concentrations were developed and compared, each implementing a different hypothesis for the evanescence of glucagon effect. The best model successfully described EGP using the glucagon-to-insulin ratio and over-basal glucose to account for the waning glucagon effect. The model precisely estimated hepatic glucagon and insulin sensitivities. However, the glucose effect was excessively delayed, likely reflecting a cascade of other biological signals rather than the direct effect of hyperglycemia on the liver.NEW & NOTEWORTHY The model can be used to quantify hepatic glucagon and insulin sensitivity, accounting also for glucagon evanescence over time. The ability to quantify glucagon effects on postprandial glucose metabolism will further our understanding of its role in the onset and progression of type 2 diabetes. These findings can also be used in the design of novel glucagon-based therapies where accurate modeling of glucagon action is required to meet efficacy and safety standards.

Recent advances and foundational knowledge are integrated to provide a comprehensive description of brain-gut signaling relevant to colorectal motility, with an emphasis on defecation. We discuss molecular targets of therapeutic potential. We identify four levels of neural control: 1) cortical and hypothalamic centers; 2) pontomedullary cell groups; 3) the lumbosacral defecation centers; and 4) the enteric nervous system (ENS). The critical role of central nervous system (CNS) input is evidenced by the constipation that follows spinal cord injury or during Parkinson's disease. The constipation of spinal cord injury suggests that propulsive reflexes generated by the ENS require augmentation from the CNS. Conversely, the crucial role of the ENS is revealed by the failed defecation in Hirschsprung and Chagas diseases. Spinal descending pathways receive inputs from the cortex and hypothalamus, and converge on a common efferent neuronal link between the CNS and the ENS: parasympathetic preganglionic neurons (PPG neurons) that connect with ENS directly or via pelvic ganglia. CNS pathways respond to the urge to defecate, to stress or alarm, and to signals from the large intestine. The ENS responds to signals from its lumen, commonly mediated through the release of local hormones, and to signals from the CNS. PPG neurons, the CNS to ENS link, express a wide range of amine and peptide receptors that are potential targets for the treatment of constipation. Important among targets are ghrelin, dopamine, and serotonin receptors. The receptors within the colon that connect luminal signals with propulsive contractile activity also represent potential therapeutic targets.