leptin and Hypercapnia

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Topics: Humans; Hypercapnia; Hypoventilation; Leptin; Obesity; Obesity Hypoventilation Syndrome

Collapsible pharyngeal airway size is determined by interaction between structural properties of the pharyngeal airway and neural regulation of the pharyngeal dilating muscles. Obesity seems to have two distinct mechanical influences on the pharyngeal airway collapsibility. First, obesity increases soft tissue surrounding the pharyngeal airway within limited maxillomandible enclosure occupying and narrowing its space (pharyngeal anatomical imbalance). Second, obesity, particularly central obesity, increases visceral fat volume decreasing lung volume. Pharyngeal wall collapsibility is increased by the lung volume reduction, possibly through decreased longitudinal tracheal traction (lung volume hypothesis). Neural compensation for functioning structural abnormalities operating during wakefulness is lost during sleep, leading to pharyngeal obstruction. Instability of the negative feedback of the respiratory system may accelerate cycling of pharyngeal closure and opening. Improvement of the pharyngeal anatomical imbalance and maintenance of lung volume are the keys for safe perioperative airway managements of obese patients with obstructive sleep apnea.

Topics: Airway Resistance; Anesthesia; Functional Residual Capacity; Humans; Hypercapnia; Leptin; Obesity; Perioperative Care; Pharyngeal Muscles; Pharynx; Sleep Apnea, Obstructive; Tongue

Obesity hypoventilation syndrome (OHS) consists of a combination of obesity and chronic hypercapnia accompanied by sleep-disordered breathing. During the last 3 decades, the prevalence of extreme obesity has markedly increased in the United States and other countries. With a global epidemic of obesity, the prevalence of OHS is bound to increase. Patients with OHS have a lower quality of life with increased health-care expenses and are at a higher risk for the development of pulmonary hypertension and early mortality compared to eucapnic patients with sleep-disordered breathing. Despite the significant morbidity and mortality associated with this syndrome, it is often unrecognized and treatment is frequently delayed. Clinicians must maintain a high index of suspicion since early recognition and treatment reduces the high burden of morbidity and mortality associated with this syndrome. In this review, we will discuss the definition and clinical presentation of OHS, provide a summary of its prevalence, review the current understanding of the pathophysiology, and discuss the recent advances in the therapeutic options.

Topics: Acetazolamide; Algorithms; Animals; Bariatric Surgery; Comorbidity; Continuous Positive Airway Pressure; Contraceptives, Oral, Synthetic; Diuretics; Humans; Hypercapnia; Leptin; Medroxyprogesterone; Obesity Hypoventilation Syndrome; Positive-Pressure Respiration; Quality of Life; Respiratory Muscles; Tracheostomy; Treatment Outcome

Leptin augments central CO. In rats at postnatal day (p)4 and p21, hyperoxic and hypercapnic ventilatory responses, and pSTAT and SOCS3 protein expression in the hypothalamus, NTS and LC were measured before and after treatment with exogenous leptin (6 µg/g).. Exogenous leptin increased the hypercapnic response in p21 but not in p4 rats (P ≤ 0.001). At p4, leptin increased pSTAT expression only in the LC, and SOCS3 expression in the NTS and LC; while at p21 pSTAT and SOCS3 levels were higher in the hypothalamus, NTS, and LC (P ≤ 0.05).. We describe the developmental profile of the effect of exogenous leptin on CO. Exogenous leptin does not augment CO

Topics: Animals; Animals, Newborn; Carbon Dioxide; Hypercapnia; Leptin; Rats; Respiration

Topics: Animals; Carbon Dioxide; Chemoreceptor Cells; Hypercapnia; Leptin; Male; Medulla Oblongata; Mice; Mice, Inbred C57BL; Neurons; Obesity; Respiration; Respiratory Mechanics; Signal Transduction; Sleep

We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study, we examined whether activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia.. Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU-9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119-treated rats as well as obese and lean MC4R-deficient rats were exposed to CIH for 7-18 consecutive days.. Chronic intermittent hypoxia reduced cumulative food intake by 18 ± 5 g while MAP and HR increased by 10 ± 3 mm Hg and 9 ± 5 bpm in untreated rats. SHU-9119 increased food intake (from 15 ± 1 to 46 ± 3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10 ± 1 vs 9 ± 1 mm Hg for untreated and SHU-9119 treated rats). In obese MC4R-deficient rats, CIH for 7 days raised BP by 11 ± 4 mm Hg. However, when MC4R-deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity.. These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia.

Topics: Animals; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Eating; Heart Rate; Hematocrit; Hypercapnia; Hypoxia; Insulin; Leptin; Male; Obesity; Pulmonary Ventilation; Rats, Sprague-Dawley; Rats, Transgenic; Receptor, Melanocortin, Type 4; Sympathetic Nervous System

Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin.. Here, we tested if MC4R also contributes to leptin's effects on respiratory function.. After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice.. Leptin (5 μg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1)  kg(-1) and SHU9119: 997 ± 67 mL min(-1)  kg(-1) , vs. PBS: 1379 ± 91 mL min(-1)  kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1)  kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice.. These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.

Topics: Animals; Body Weight; Carbon Dioxide; Gene Expression Regulation; Hypercapnia; Leptin; Male; Melanocortins; Melanocyte-Stimulating Hormones; Mice; Mice, Knockout; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Respiratory Physiological Phenomena

Previous studies showed that leptin-deficient (ob/ob) mice develop obesity and impaired ventilatory responses to CO(2) (V(E) - CO(2)). In this study, we examined if leptin replacement improves chemorespiratory responses to hypercapnia (7 % CO(2)) in ob/ob mice and if these effects were due to changes in body weight or to the direct effects of leptin in the central nervous system (CNS). V(E) - CO(2) was measured via plethysmography in obese leptin-deficient- (ob/ob) and wild-type- (WT) mice before and after leptin (10 μg/2 μl day) or vehicle (phosphate buffer solution) were microinjected into the fourth ventricle for four consecutive days. Although baseline V(E) was similar between groups, obese ob/ob mice exhibited attenuated V(E) - CO(2) compared to WT mice (134 ± 9 versus 196 ± 10 ml min(-1)). Fourth ventricle leptin treatment in obese ob/ob mice significantly improved V(E) - CO(2) (from 131 ± 15 to 197 ± 10 ml min(-1)) by increasing tidal volume (from 0.38 ± 0.03 to 0.55 ± 0.02 ml, vehicle and leptin, respectively). Subcutaneous leptin administration at the same dose administered centrally did not change V(E) - CO(2) in ob/ob mice. Central leptin treatment in WT had no effect on V(E) - CO(2). Since the fourth ventricle leptin treatment decreased body weight in ob/ob mice, we also examined V(E) - CO(2) in lean pair-weighted ob/ob mice and found it to be impaired compared to WT mice. Thus, leptin deficiency, rather than obesity, is the main cause of impaired V(E) - CO(2) in ob/ob mice and leptin appears to play an important role in regulating chemorespiratory response by its direct actions on the CNS.

Topics: Animals; Brain Stem; Carbon Dioxide; Homozygote; Hypercapnia; Injections, Intraventricular; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pulmonary Ventilation

Acute experiments on anesthetized laboratory rats were performed to study the effects microinjections of 10(-4) M leptin into the solitary tract nucleus on the extent of the Hering-Breuer inflation reflex in ventilatory reactions to hypercapnia. Local administration of leptin into this area led to inhibition of the Hering-Breuer reflex. The extent of ventilatory responses to hypercapnia, conversely, increased, which may provide evidence that leptin has a modulatory influence on central chemoreceptors. These physiological mechanisms of action probably play a leading role in mediating the stimulatory respiratory effects of leptin at the level of the solitary tract nucleus.

Topics: Animals; Electromyography; Female; Hypercapnia; Leptin; Male; Microinjections; Rats; Reflex, Stretch; Respiration; Respiratory Center; Solitary Nucleus

In acute experiments on anaesthetised rats we investigated the effects of 10(-4) M leptin microinjected into the solitary tract nucleus on inspiratory-terminating Breuer-Hering reflex and ventilatory responses to hypercapnea. We found that the local administration of leptin into the area inhibited the inspiratory-terminating Breuer-Hering reflex. In contrast, ventilatory responses to hypercapnea were accentuated suggesting a modulatory effect of leptin on central chemoreceptors. The discovered physiological mechanisms are likely to play a key role for stimulating respiratory effects of leptin at the level of the solitary tract nucleus.

Topics: Animals; Electromyography; Female; Hypercapnia; Leptin; Male; Microinjections; Rats; Reflex, Stretch; Respiration; Respiratory Center; Solitary Nucleus

Leptin levels have been reported to be higher in patients with obstructive sleep apnea (OSA) than in control subjects with matching age and body mass index (BMI). Although animal studies have shown that leptin augments hypercapnic ventilatory response (HCVR), the effect of leptin on HCVR has not been clarified in OSA.. To investigate whether leptin could augment HCVR during wakefulness in patients with OSA.. Of 134 consecutive patients with OSA, 13 eucapnic and 16 hypercapnic patients with OSA, and 12 control subjects matched for sex, age, and BMI were selected. Fasting serum leptin levels were collected, and HCVR during wakefulness assessed by the slope between minute ventilation and end-tidal PCO(2).. There was a significant positive relationship between serum leptin levels and HCVR in the group including control subjects and eucapnic patients with OSA (r = 0.42, p < 0.05). Subgroup analyses suggest that serum leptin levels and HCVR were significantly higher in eucapnic patients with OSA than in control subjects. On the other hand, hypercapnic patients had lower HCVR than eucapnic patients (p < 0.05), whereas serum leptin levels were similar between the two OSA subgroups.. Leptin levels and HCVR are correlated as long as the eucapnic condition is maintained. We speculate that a stimulating effect of leptin on HCVR may be masked by the hypoventilation state.

Topics: Body Mass Index; Carbon Dioxide; Comorbidity; Humans; Hypercapnia; Hypoventilation; Leptin; Polysomnography; Respiratory Muscles; Sleep Apnea, Obstructive; Wakefulness

Topics: Adult; Carbon Dioxide; Comorbidity; Humans; Hypercapnia; Hypoventilation; Leptin; Male; Middle Aged; Obesity; Respiration; Sleep Apnea, Obstructive; Work of Breathing

Long-term nocturnal non-invasive mechanical ventilation (NIMV) is an effective treatment for obesity-hypoventilation syndrome (OHS), improving central carbon dioxide (CO(2)) sensitivity. Leptin might contribute to sustain adequate ventilation in obesity. The aim of the study was to investigate the role of leptin in the OHS pathogenesis looking at its relationship to CO(2) sensitivity before and after NIMV in OHS patients.. In six obese patients (3F/3M; aged 63+/-9 yr; BMI 47.0+/-4.5 kg/m(2)) with OHS and without obstructive sleep apnoea-hypopnoea (OSAH) diurnal arterial blood gases, fasting plasma leptin concentration and CO(2) chemosensitivity were determined before and after 10.3+/-5.6 (range 6-20) months of NIMV.. After NIMV improvements were observed in gas exchange (PaO(2) from 51.3+/-6.7 to 75.0+/-10.3 mmHg, p<0.01; PaCO(2) from 55.5+/-4.8 to 43.7+/-1.2 mmHg, p<0.01; [HCO(3)(-)] from 33.3+/-3.8 to 29.8+/-1.7 mmol/l, p<0.05) and CO(2) chemosensitivity, measured as P(0.1)/PetCO(2) slope (from 0.09+/-0.07 to 0.18+/-0.07 cmH(2)O/mmHg, p<0.05) and V(E)/PetCO(2) slope (from 0.4+/-0.3 to 0.9+/-0.5l/min/mmHg, p=0.07). Plasma leptin increased from 34.5+/-21.1 ng/ml to 50.2+/-22.9 ng/ml (p<0.01) after NIMV and changes of the P(0.1)/PetCO(2) slope correlated with percent changes of plasma leptin (r(2)=0.79, p<0.05).. These findings suggest a possible role of leptin in the recovery of neuromuscular response to hypercapnia obtained during long-term nocturnal NIMV in OHS patients without OSAH.

Topics: Aged; Anthropometry; Carbon Dioxide; Circadian Rhythm; Fasting; Female; Follow-Up Studies; Humans; Hypercapnia; Leptin; Male; Middle Aged; Obesity Hypoventilation Syndrome; Oxygen; Partial Pressure; Pilot Projects; Pulmonary Gas Exchange; Respiration, Artificial

Leptin is a powerful stimulant of ventilation in rodents. In humans, resistance to leptin has been consistently associated with obesity. Raised leptin levels have been reported in subjects with sleep apnoea or obesity-hypoventilation syndrome. The aim of the present study was to assess, by multivariate analysis, the possible association between respiratory centre impairment and levels of serum leptin. In total, 364 obese subjects (body mass index >or=30 kg.m(-2)) underwent the following tests: sleep studies, respiratory function tests, baseline and hypercapnic response (mouth occlusion pressure (P(0.1)), minute ventilation), fasting leptin levels, body composition and anthropometric measures. Subjects with airways obstruction on spirometry were excluded. Out of the 346 subjects undergoing testing, 245 were included in the current analysis. Lung volumes, age, log leptin levels, end-tidal carbon dioxide tension, percentage body fat and minimal nocturnal saturation were predictors for baseline P(0.1). The hypercapnic response test was performed by 186 subjects; log leptin levels were predictors for hypercapnic response in males, but not in females. Hyperleptinaemia is associated with a reduction in respiratory drive and hypercapnic response, irrespective of the amount of body fat. These data suggest the extension of leptin resistance to the respiratory centre.

Topics: Adult; Body Composition; Chi-Square Distribution; Female; Humans; Hypercapnia; Hypoventilation; Leptin; Linear Models; Male; Obesity; Polysomnography; Respiratory Function Tests; Respiratory Mechanics; Statistics, Nonparametric

Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. In obese humans, serum leptin is up to four times higher than in lean subjects, indicating that human obesity is associated with a central resistance to the weight-lowering effects of leptin. Although the leptin-deficient mouse (ob/ob) develops obesity hypoventilation syndrome (OHS), in humans with OHS, serum leptin is a better predictor of awake hypercapnia in obesity than the body mass index (BMI). This suggests that central leptin resistance may promote the development of OHS in humans. We speculated that the reversal of OHS by regular non-invasive ventilation (NIV) therapy decreases leptin levels.. The aim of this study was to investigate whether ventilatory treatment of OHS would alter circulating leptin concentrations.. We measured fasting serum leptin levels, BMI, spirometry and arterial blood gases in 14 obese hypercapnic subjects undergoing a diagnostic sleep study.. The average age of the subjects was (mean +/- SE) 62 +/- 13 years, BMI 40.9 +/- 2.2 kg/m(2), PaCO(2) 6.7 +/- 0.2 kPa, PaO(2 )8.9 +/- 0.4 kPa and total respiratory disturbance index 44 +/- 35 events/hour. Subjects were clinically reviewed after a median of 2.3 years (range 1.6-3) with repeat investigations. Nine patients were regular NIV users and 5 were non-users. NIV users had a significant reduction in serum leptin levels (p = 0.001), without a change in BMI. In these patients, there was a trend towards an improved daytime hypercapnia and hypoxemia, while in the 5 non-users, no changes in serum leptin, BMI or arterial blood gases occurred.. Regular NIV use reduces serum leptin in OHS. Leptin may be a modulator of respiratory drive in patients with OHS.

Topics: Body Mass Index; Carbon Dioxide; Continuous Positive Airway Pressure; Female; Humans; Hypercapnia; Hypoventilation; Hypoxia; Leptin; Male; Middle Aged; Obesity; Oxygen; Polysomnography; Positive-Pressure Respiration; Prospective Studies; Sleep Apnea, Obstructive; Syndrome

Obesity and visceral fat accumulation (VFA) are risk factors for the development of obstructive sleep apnea-hypopnea syndrome (OSAHS), and a subgroup of OSAHS patients acquire hypoventilation. Circulating leptin, an adipocyte-derived signaling factor, increases in accordance with body mass index (BMI); under experimental conditions, leptin selectively decreases visceral adiposity and it is also a respiratory stimulant.. To investigate whether the location of body fat deposits, ie, the distribution of VFA and subcutaneous fat accumulation (SFA), contributes to hypoventilation and whether circulating levels of leptin are involved in the pathogenesis of hypoventilation, which is often observed in OSAHS.. We assessed VFA and SFA by abdominal CT scan, and measured lung function and circulating levels of leptin in 106 eucapnic and 79 hypercapnic male patients with OSAHS.. In the whole study group, circulating leptin levels correlated with BMI (r = 0.56), VFA (r = 0.24), and SFA (r = 0.47), but not with Po(2) or sleep mean arterial oxygen saturation (Sao(2)). BMI, percentage of predicted vital capacity, FEV(1)/FVC ratio, apnea-hypopnea index, sleep mean Sao(2), VFA, and SFA were not significantly different between two groups. Circulating leptin levels were higher in the hypercapnic group than in the eucapnic group. Logistic regression analysis indicated that serum leptin was the only predictor for the presence of hypercapnia (beta = 0.21, p < 0.01).. These results suggest that the location of body fat deposits may not contribute to the pathogenesis of hypoventilation, and circulating leptin may fail to maintain alveolar ventilation in hypercapnic patients with OSAHS.

Topics: Adipose Tissue; Adult; Aged; Body Composition; Body Mass Index; Humans; Hypercapnia; Hypoventilation; Leptin; Logistic Models; Male; Middle Aged; Oxygen; Polysomnography; Risk Factors; Skinfold Thickness; Sleep Apnea, Obstructive; Statistics as Topic

To investigate the relationship between fetoplacental leptin secretion and blood gases.. We measured the levels of umbilical arterial and venous leptin, umbilical cord gas, umbilical venous blood glucose, and estradiol-17beta (E2) in 89 pregnant women. Correlation between the leptin levels and other variables (gestational age, birth weight, maternal body weight, height, body mass index, maternal body weight gain, placental weight, umbilical cord gas data, and levels of umbilical venous blood glucose and E2) were examined statistically.. Umbilical arterial and venous leptin levels were 7.64 +/- 12.76 and 7.76 +/- 13.17 (ng/mL), respectively, correlating positively with carbon dioxide pressure levels (r = 0.446, P <.001; r = 0.406, P <.001, respectively) and correlating inversely with pH (r = -0.337, P =.001; r = -0.247, P =.019, respectively). Umbilical venous glucose, E2, and other factors did not correlate with leptin levels.. Leptin secretion into the fetoplacental circulation may be associated with fetal hypercapnia, suggesting two important roles for leptin: one for basal control of fetal fat tissue and one as an acute stress-related hormone.

Topics: Adult; Blood Glucose; Carbon Dioxide; Estradiol; Female; Fetal Diseases; Humans; Hypercapnia; Leptin; Placental Circulation; Pregnancy; Stress, Physiological

Human obesity leads to an increase in respiratory demands. As obesity becomes more pronounced some individuals are unable to compensate, leading to elevated arterial carbon dioxide levels (PaCO2), alveolar hypoventilation, and increased cardiorespiratory morbidity and mortality (Pickwickian syndrome). The mechanisms that link obesity and hypoventilation are unknown, but thought to involve depression of central respiratory control mechanisms. Here we report that obese C57BL/6J-Lepob mice, which lack circulating leptin, also exhibit respiratory depression and elevated PaCO2 (> 10 mm Hg; p < 0. 0001). A role for leptin in restoring ventilation in these obese, mutant mice was investigated. Three days of leptin infusion (30 microg/d) markedly increased minute ventilation (V E) across all sleep/wake states, but particularly during rapid eye movement (REM) sleep when respiration was otherwise profoundly depressed. The effect of leptin was independent of food intake, weight, and CO2 production, indicating a reversal of hypoventilation by stimulation of central respiratory control centers. Furthermore, leptin replacement in mutant mice increased CO2 chemosensitivity during non-rapid eye movement (NREM) (4.0 +/- 0.5 to 5.6 +/- 0.4 ml/min/%CO2; p < 0.01) and REM (-0.1 +/- 0.5 to 3.0 +/- 0.8 ml/min/%CO2; p < 0.01) sleep. We also demonstrate in wild-type mice that ventilation is appropriately compensated when obesity is diet-induced and endogenous leptin levels are raised more than tenfold. These results suggest that leptin can prevent respiratory depression in obesity, but a deficiency in central nervous system (CNS) leptin levels or activity may induce hypoventilation and the Pickwickian syndrome in some obese subjects. O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity.

Topics: Animals; Arteries; Carbon Dioxide; Hypercapnia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Proteins; Respiration