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Dr. Marik is Director, Medical Intensive Care Unit, Washington Hospital Center.
Correspondence to: Paul E. Marik, MD, FCCP, Department of Internal Medicine, RM-2A-68, Washington Hospital Center, 110 Irving Street, NW, Washington, DC 20010-2975; e-mail: pem4{at}mhg.edu
The United States has the notable distinction of having the highest concentration of obese individuals in the world, with a staggering 55% of the adult population being overweight1 2 3 The body mass index (BMI; weight in kilograms divided by the square of height in meters) is widely used to distinguish between obese and nonobese adults. Overweight is defined as a BMI measure of 25.0 to 29.9 and obesity as a BMI measure of 30.0 or greater. Excess weight is a major health hazard, with the risk of death from all causes, cardiovascular disease, and cancer increasing throughout the range of moderate and severe overweight for both men and women in all age groups.4 In recent years, body circumference indexes (eg, waist circumference, waist-to-height circumference ratio, waist-to-hip circumference ratio) have been advocated because they can identify adults with a central (android) pattern of obesity, who are at higher risk of obesity-related health problems, independent of the BMI.5 6
Excess body fat has several effects on the respiratory system—most
notably, a decline in the expiratory reserve volume and an increase in
the FEV1/FVC ratio.7
8
The vital
capacity (
C), total lung capacity (TLC), and functional residual
volume (FRV) are generally maintained in otherwise normal individuals
with mild-to-moderate obesity but are reduced by up to 30% in morbidly
obese patients.7
8
9
The work of breathing (WOB) is
increased by abnormal chest elasticity, increased chest wall
resistance, increased airway resistance (Raw), abnormal diaphragmatic
position, and upper airway resistance, as well as by the need to
eliminate a higher daily production of carbon
dioxide.7
10
11
Severely obese patients are often
hypoxemic, with a widened alveolar-arterial oxygen gradient, caused
primarily by ventilation-perfusion (/
)
mismatching.7
12
In addition, obesity is a major risk
factor for the development pulmonary thromboembolism.13
The obstructive sleep apnea (OSA) syndrome OSA is a disabling condition characterized by excessive daytime sleepiness, disruptive snoring, repeated episodes of upper airway obstruction during sleep, and nocturnal hypoxemia. OSA occurs in 4 to 9% of middle-aged men and in 1 to 2% of middle-aged women.14 Obesity is a major risk factor for OSA, occurring in up to 50% of obese men.14 15
The etiology of obesity is heterogeneous, with several factors having the potential to cause a positive energy balance over long periods. These factors include a high-fat diet, a low level of habitual physical activity, a low resting metabolic rate for a given body mass and body composition, a high respiratory quotient in the fasting state (ie, a tendency to oxidize more carbohydrates than lipids under standardized conditions), and perhaps high insulin sensitivity. Interest in the pathophysiology of obesity has recently intensified with the discovery of leptin, the anti-obesity hormone.16 17 18 Leptin, a protein of 167-amino acids, has a structure similar to that of cytokines. The hormone is produced predominantly in white adipose tissue. Leptin levels increase exponentially with increasing fat mass. Leptin circulates in the plasma in a free-form state or bound to leptin-binding proteins. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate neuroendocrine function, energy intake, and expenditure. Leptin inhibits the synthesis of hypothalamic neuropeptide Y (NPY), a potent stimulator of food intake.19 20 In addition, downregulation of NPY results in increased sympathetic nervous system outflow and energy expenditure. Furthermore, increasing leptin levels activate the thyroid, growth hormone, and gonadal axes and suppress the pituitary-adrenal axis. Leptin also has an effect on peripheral tissues. Leptin directly inhibits intracellular lipid by reducing fatty-acid and triglyceride synthesis and, concomitantly, by increasing lipid oxidation.21 This effect on lipid metabolism may be mediated by an inhibitory effect of leptin on acetyl-CoA carboxylase activity, the rate-limiting enzyme in fatty-acid synthesis.
Most obese subjects have high circulating leptin levels, indicating that, in most circumstances, obesity is a leptin-resistant state. Much like type II diabetes, it is possible that receptor or post-receptor defects could be responsible for leptin resistance in obese subjects. Treatment with subcutaneous leptin reduces weight in all mammalian species tested.22 Leptin-induced weight loss is completely specific for loss of adipose tissue, whereas food restriction results in loss of both adipose tissue and lean body mass.22 Furthermore, in animal studies leptin selectively decreases visceral adiposity.23 Despite the demonstration of leptin resistance in most obese humans, subcutaneous recombinant leptin induces a significant dose-dependent reduction in fat mass and weight loss in these subjects.24
Mutant obese C57BL/6-J-Lepob mice, which lack circulating leptin,
exhibit respiratory depression and elevated
PaCO2.25
26
An infusion
of leptin into these animals markedly increases minute ventilation
(E) across all sleep/wake states and improves lung
mechanics.25
26
These studies suggest that both obesity
and OSA may be due to leptin resistance. In this issue of
CHEST (see page 580), Ip and colleagues have demonstrated
that obese subjects with OSA have significantly higher levels of leptin
when compared with weight-matched BMI controls. Interestingly, subjects
treated with nasal continuous positive airway pressure (nCPAP) for 6
months demonstrated significant reductions in circulating leptin
levels. This supports the findings of Chin and colleagues who, in
addition to demonstrating a fall of leptin levels with nCPAP,
demonstrated significant reductions in visceral fat
accumulation.27
This raises the intriguing
possibility that treatment of OSA with nCPAP may reverse the leptin
receptor abnormality found in this disorder. This would suggest that
nCPAP, as well as exogenous leptin agonists or agents that restore
leptin receptor sensitivity, may have roles in reversing the primary
pathophysiologic abnormalities of the obesity-OSA syndrome.
References
This article has been cited by other articles:
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  F. Jurysta, J.-P. Lanquart, P. van de Borne, P.-F. Migeotte, M. Dumont, J.-P. Degaute, and P. Linkowski The link between cardiac autonomic activity and sleep delta power is altered in men with sleep apnea-hypopnea syndrome Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1165 - R1171. [Abstract] [Full Text] [PDF]
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 I.A. Harsch, P.C. Konturek, C. Koebnick, P.P. Kuehnlein, F.S. Fuchs, S. Pour Schahin, G.H. Wiest, E.G. Hahn, T. Lohmann, and J.H. Ficker Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment Eur. Respir. J., August 1, 2003; 22(2): 251 - 257. [Abstract] [Full Text] [PDF]
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