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Pittsburgh, PA
Dr. Atwood is Assistant Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine and the Veterans Affairs Pittsburgh Healthcare System.
Correspondence to: Charles W. Atwood, MD, FCCP, Division of Pulmonary, Allergy, and Critical Care Medicine, NW628 MUH, University of Pittsburgh School of Medicine, Pittsburgh, PA; e-mail: atwoodcw{at}upmc.edu
Occasionally, scientific discoveries shape our understanding of medicine and physiology in broad and multifaceted ways that have important implications across disciplines. More than 2 decades ago, the discovery of nitric oxide (NO), and its subsequently elucidated role in vascular homeostasis, was such an example. Discovery of NO has had profound effects on clinical medicine in fields as diverse as pulmonary and critical care medicine, transplantation, infectious diseases, and cardiology. Important advances in our understanding of disorders ranging from sepsis to asthma to hypertension to organ transplantation have been made in the past decade based on our growing understanding of NO function.12
A more recent example of a paradigm-changing discovery has been the characterization and our growing understanding of the hormone leptin. This adipocyte-derived hormone is an example of another biological agent with broad, pleiotropic effects in human physiology, pathophysiology and, likely in the near future, therapeutics. A rapidly growing literature about leptin highlights its important role in a number of areas of physiology, ranging from maintenance of body mass and energy expenditure, to vascular and sympathetic nervous system regulation, to regulation of ventilation.345 Leptin has also recently been implicated in hypothalamic amenorrhea, both as contributing cause in a deficiency state and, as a potential therapy, through administration of recombinant leptin.6 Clinicians and scientists with interests in pulmonary medicine and respiratory physiology, neuroscience, respiratory neurobiology, endocrinology, and obesity have all claimed a "piece of the leptin pie" as their own.
In the context of respiratory and sleep physiology, leptin is important because of its effect on ventilation and weight homeostasis. Early studies using rodent models highlighted the possible role of leptin in disorders of ventilation, such as obstructive sleep apnea (OSA) and obesity-hypoventilation disorder. In the leptin-deficient Ob/Ob mouse, absence of leptin is associated with severe obesity, hypoventilation, and decreased ventilatory responsiveness to hypercapnia.7 Administration of exogenous leptin in the leptin-deficient mouse resulted in augmentation of ventilation back toward the normal state.8
In humans, the role of leptin in regulation of ventilation is less clear. Leptin levels in obese humans tend to be increased, rather than low, suggesting that obesity in humans is a state of leptin resistance. Circulating leptin levels in humans vary directly with fat stores (and body mass index [BMI]). This makes it a natural target for studies seeking to understand the relationship between obesity and sleep-disordered ventilation. In one recently published sleep laboratory-based study,9 investigators found elevated leptin levels in 56 obese men and women. Leptin was a better predictor of hypercapnia in these subjects than were other measures of obesity such as percentage of body fat.
Increased body weight is an important risk factor for OSA. Fat surrounding the upper airway has been identified as a factor in sleep apnea pathogenesis due to mass loading of the upper airway.10 However, a previously unexplained finding is the heterogeneous ventilatory response to obesity in OSA patients. For many years, obesity has been considered a necessary factor for hypoventilation in OSA but not sufficient to account for it alone. This is because the majority of obese individuals with OSA do not hypoventilate more than nonobese individuals during sleep.11 What distinguishes patients with obesity and OSA with hypoventilation from patients with obesity and OSA without hypoventilation has not been clear.511 Therefore, with our growing understanding of leptin and its potential role in control of ventilation, it is very logical to consider leptin as a possible mediator in the obesity-ventilation relationship.
To further our understanding about the relationship between leptin, obesity, fat distribution, and OSA, Shimura and colleagues12 reported the results of an investigation in which they studied a sleep laboratory patient cohort of Japanese men with OSA. These 426 subjects were classified into a eucapnic group (PCO2 
45 mmHg; n = 327) and a hypercapnic group (n = 79). From the eucapnic patient group, they were able to match 106 subjects for BMI and age with values virtually the same as those found in the hypercapnic group (BMI, 33.0 ± 0.4 vs 33.2 ± 0.8; age, 43.5 ± 1.4 years vs 44.2 ± 1.1 years [mean ± SD]). Severity of sleep apnea was comparable between the two groups: the apnea-hypopnea index (AHI) for the eucapnic group was 52.9 ± 2.2/h, and the AHI for the hypercapnic subjects was 47.4 ± 2.8/h (p > 0.05). Abdominal CT scans were also performed for quantitative measurement of fat stores in the subcutaneous and visceral compartments. When the investigators compared leptin levels between the hypercapnic and eucapnic groups, they found that the hypercapnic group (average PCO2, 46.6 ± 0.4 mm Hg) had a significantly higher leptin level compared to the eucapnic group (average PCO2, 40.9 ± 0.3 mm Hg). Using logistic regression analysis, Shimura et al12 found that leptin level was the only variable predictive of hypoventilation in Japanese men with OSA. BMI, measures of OSA severity (AHI, mean arterial oxygen saturation during sleep), and visceral or subcutaneous fat measurements were not predictive of hypercapnia.
The study by Shimura et al12 adds to our knowledge of the role of differential fat accumulation and its effect on leptin and hypoventilation. In this study, subcutaneous fat had a stronger association with circulating leptin levels in both eucapnic and hypercapnic subjects than did visceral fat levels. This study extends the findings of an earlier study9 by comparing respective distributions of visceral and subcutaneous fat and their association with leptin and hypoventilation.
Gender is also evolving as an important mediator in the relationship between leptin and ventilatory drive. Polotsky and others7 found that leptin-deficient female mice showed decreased hypercapnic ventilatory responsiveness compared to leptin-deficient males of the same strain during wakefulness and non-rapid eye movement sleep. In wild-type mice (with normal leptin levels), they demonstrated that female mice showed a blunted hypercapnic ventilatory response in rapid eye movement sleep compared to males of the same strain. These animal data suggest that leptin may have a differential effect on ventilation based on gender. Human females also tend to have more subcutaneous fat as compared to males, who tend to have more visceral fat. Thus, greater subcutaneous fat stores in females may account for their higher leptin levels compared to human males with a comparable degree of overall obesity,4 and put them at greater risk for hypoventilation during sleep.
Given these findings, what might the mechanisms be that explain the association of leptin with hypoventilation in obese OSA subjects? Unfortunately, much remains to be learned. Some have speculated that impaired transport across the blood-brain barrier may be one mechanism of a peripheral/central leptin imbalance in obesity.713 Another explanation is impairment in central leptin signaling. This latter mechanism could include down-regulation of central leptin receptors, defects in a second messenger system, or influences from other molecules such as neuropeptide Y, which acts in opposition to leptin in appetite and weight homeostasis,14 or a combination of these defects.
At this time, we can conclude that leptin may have an important role in mediating hypoventilation during sleep and the subsequent development of hypercapnia in some individuals with OSA. The study by Shimura et al12 adds to our understanding of the role of leptin in ventilation homeostasis in obesity and its relationship to the different types of fat accumulation in patients with OSA. However, more work still lies ahead to complete our understanding of the fascinating and multifaceted role of leptin in regulation of weight and ventilation in humans.
Acknowledgements
The author thanks Drs. Christopher O’Donnell, Mark Sanders, and Patrick Strollo in the writing of this editorial.
Footnotes
You may have noticed that recent journals have been exceptionally large. This increase in the number of articles per issue is short term. We are temporarily increasing the size of the journal to decrease time from acceptance to publication, eliminate backlog, phase out an old manuscript system, and prepare for changes beginning with the January 2006 issue.
Richard S. Irwin, MD, FCCPEditor in Chief, CHEST
References
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