Abdominal fat and sleep apnea: the chicken or the egg?

Obstructive sleep apnea (OSA) syndrome is a disorder characterized by repetitive episodes of upper airway obstruction that occur during sleep. Associated features include loud snoring, fragmented sleep, repetitive hypoxemia/hypercapnia, daytime sleepiness, and cardiovascular complications. The prevalence of OSA is 2-3% and 4-5% in middle-aged women and men, respectively. The prevalence of OSA among obese patients exceeds 30%, reaching as high as 50-98% in the morbidly obese population. Obesity is probably the most important risk factor for the development of OSA. Some 60-90% of adults with OSA are overweight, and the relative risk of OSA in obesity (BMI >29 kg/m(2)) is >or=10. Numerous studies have shown the development or worsening of OSA with increasing weight, as opposed to substantial improvement with weight reduction. There are several mechanisms responsible for the increased risk of OSA with obesity. These include reduced pharyngeal lumen size due to fatty tissue within the airway or in its lateral walls, decreased upper airway muscle protective force due to fatty deposits in the muscle, and reduced upper airway size secondary to mass effect of the large abdomen on the chest wall and tracheal traction. These mechanisms emphasize the great importance of fat accumulated in the abdomen and neck regions compared with the peripheral one. It is the abdomen much more than the thighs that affect the upper airway size and function. Hence, obesity is associated with increased upper airway collapsibility (even in nonapneic subjects), with dramatic improvement after weight reduction. Conversely, OSA may itself predispose individuals to worsening obesity because of sleep deprivation, daytime somnolence, and disrupted metabolism. OSA is associated with increased sympathetic activation, sleep fragmentation, ineffective sleep, and insulin resistance, potentially leading to diabetes and aggravation of obesity. Furthermore, OSA may be associated with changes in leptin, ghrelin, and orexin levels; increased appetite and caloric intake; and again exacerbating obesity. Thus, it appears that obesity and OSA form a vicious cycle where each results in worsening of the other.

We thank Dr. Oltmanns for the important, eye-opening comments raised in her online letter to the editor (1). Indeed, in our article we discuss the complex relationships between obesity/abdominal fat and sleep disordered breathing (SDB) (2). While the effects of obesity on upper airway collapsibility are well established, the potential SDB-induced weight gain is less understood.

The major processes in obstructive sleep apnea (OSA) are sleep fragmentation (and consequently daytime somnolence and sympathetic nerve activation) and intermittent hypoxia/reoxygenation (and consequently oxidative stress, reactive oxygen species formation, and inflammatory response). Sleep fragmentation can lead to effective sleep deprivation, daytime somnolence, reduced physical activity, and eventually weight gain. The effects of intermittent hypoxia are less obvious. Acute hypoxia has been recently shown to result in reduced resting energy expenditure (3), which, as stated by Oltmanns, may partially relate to weight gain in patients with OSA. However, these patients have been shown to demonstrate an increased metabolic rate, which is probably due to the increased work of breathing associated with recurrent upper airway collapse and elevated respiratory effort against obstructed airway (4).

As mentioned in Oltmanns’ letter, insulin resistance is one important mechanism that may lead to weight gain in patients with OSA. Although the underlying mechanism resulting in insulin resistance in patients with OSA is not fully understood, several options, such as effective sleep deprivation and elevated sympathetic activity, may play a role. Concerning the role of hypoxia, we described the study by Polotsky et al. (5) who suggest that the increase in insulin resistance in response to prolonged intermittent hypoxia was dependent on the disruption of leptin pathways. The study mentioned in Oltmanns’ letter (6) examined the effects of acute hypoxia (of 30 min duration) on glucose tolerance in 14 healthy men under the conditions of a euglycemic clamp. Their finding that acute hypoxia results in glucose intolerance is of great interest and importance and may relate to the insulin resistance observed in patients with OSA, albeit in the latter case the hypoxia is of shorter duration and with a characteristic intermittent pattern. In addition, their finding of elevated epinephrine release with hypoxia suggests that sympathetic activation may play a role in the glucose intolerance they reported.

Thus, it seems that indeed the relationships between OSA and obesity are complex. We thank Dr. Oltmanns for her important comments that further emphasize the complexity of this issue, which indisputably requires further investigation.