The inspiratory dilator phasic upper airway muscles are activated during inspiration and counteract the collapsing influence of negative airway pressure. The genioglossus is the best studied such muscle. The activity of the genioglossus is substantially reduced during expiration when pressure inside the airway becomes positive and there are fewer tendencies for collapse.

Other muscles such as the tensor palatini do not consistently demonstrate inspiratory phasic activity but instead maintain a relatively constant level of activity throughout the respiratory cycle. These are called tonic, or postural muscles, and are also thought to play a role in the maintenance of airway patency.

Negative pressure in the pharynx which would tend to collapse the airway markedly activates these muscles, which in turn counteracts this collapsing influence 65 — In patients with sleep apnea having anatomically small airways, a negative pressure reflex is substantially activated during wakefulness, leading to augmented dilator muscle activity as a neuromuscular compensatory mechanism to protect the airways Therefore, the individual's propensity for upper airway collapse during sleep depends on two variables: 1 the patient's predisposing anatomy and 2 the level of pharyngeal dilator muscle activity.

The effect of sleep on upper airway muscle activity probably plays an important role in the pathophysiology of OSA. The protective reflex activation of these muscles that can be observed during wakefulness is markedly diminished during sleep. This reflex-driven augmentation of dilator muscle activity compensates for deficient anatomy in apnea patients during wakefulness.

During sleep, there is a marked attenuation or loss of this reflex mechanism, even in normal subjects. Thus, the loss of the negative pressure reflex protecting mechanism with the reduced dependency of dilator muscle activation in negative pressure and rising CO 2 lead to falling dilator muscle activity and airway collapse 67 , 68 , 71 , The effect of obesity on upper airway dilator protecting muscle activation probably plays a substantial role in the tendency of obese individuals toward airway collapse.

Several studies reported decreased upper airway muscle protective force or altered muscle structure due to fatty deposits within the muscle 46 , 73 , This may result in increased collapsible velopharynx during wakefulness in obese individuals, which may predispose to upper airway obstruction during sleep.

Indeed, it has been clearly shown that obesity is associated with increased upper airway collapsibility, with dramatic improvement after weight reduction 41 , Velopharygeal compliance was found to be strongly correlated with neck circumference and BMI Thus, that obesity can result in upper airway collapsibility and vulnerability to OSA is well established.

The major causes are briefly presented in Fig. However, recent evidence suggests that OSA can also predispose individuals to gain weight.

These mechanisms are displayed on the left side of Fig. Numerous studies have pointed out the reduced sleep efficiency and non-refreshing nature of sleep in patients with sleep apnea. Sleep is fragmented, with reduced slow-wave sleep and REM sleep, and one of the most prominent symptoms of OSA is excessive daytime somnolence 76 — Although not strongly correlated, increasing severity of OSA results in both subjective and objective sleepiness, which can consequently result in increased prevalence of occupational and traffic accidents 82 — Daytime sleepiness may result in decreased mood and decreased physical activity, which if not associated with reduced caloric intake, will obviously worsen obesity.

Indeed, it has been shown that obesity and OSA are associated with reduced physical activity, which increases after weight reduction surgery Thus, theoretically patients with OSA are at high risk of gaining weight and subsequently worsening their OSA.

When treated, patients manage to improve alertness and daytime activity 80 , If remained untreated, some patients tend to gain weight and the apnea becomes worse 34 , The metabolic balance of sleep apnea and obesity seems to result from a complex balance between several regulatory hormones.

It is well established that sleep deprivation decreases glucose tolerance and results in insulin resistance 91 — A growing body of epidemiological evidence supports an association between chronic partial sleep deprivation short sleep duration and the risk for obesity, insulin resistance, and diabetes Sleep deprivation for 24 h decreased the insulin sensitivity in healthy subjects without changes in cortisol levels It was suggested that sleep deprivation results in decreased insulin sensitivity at peripheral receptor sites, which can eventually lead to insulin exhaustion at pancreatic sites, after longer periods of sleep deprivation Because OSA is associated with sleep fragmentation, effectively sleep loss and daytime sleepiness, the insulin sensitivity in patients has been assessed and indeed insulin resistance has been reported 95 — That OSA is an independent risk factor for increased insulin resistance can be learned from improvement in insulin sensitivity after 3 months but not 2 days of treatment with continuous positive airway pressure CPAP However, the exact mechanism leading to insulin resistance in patients with OSA is not fully understood.

One option is the effective sleep deprivation associated with OSA, and an additional potential mechanism may involve the elevated sympathetic activity in OSA In a later and larger scale study by the same group, the authors reported that insulin sensitivity significantly increased after 2 days and remained stable after 3 months of CPAP treatment.

The improvement in insulin sensitivity in the short-term treatment 2 days was more marked in less obese patients. The authors suggested that in obese individuals, insulin sensitivity is mainly determined by obesity as they were less affected by CPAP and to a lesser extent by OSA To learn about the mechanism of insulin resistance in OSA, Polotsky et al.

In lean mice, intermittent hypoxia resulted in a decrease in fasting blood glucose levels, improvement in glucose tolerance without a change in serum insulin levels, and an increase in serum leptin levels in comparison with control.

Leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by an increase in serum insulin levels, which was abolished by prior leptin infusion.

Obese mice exposed to intermittent hypoxia for 12 weeks long term developed a time-dependent increase in fasting serum insulin levels and worsening glucose tolerance, indicating insulin resistance.

The authors concluded that the increase in insulin resistance in response to prolonged intermittent hypoxia was dependent on the disruption of leptin pathways In a recent study of humans with OSA, Babu et al.

Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating and control of body weight and fat distribution Table 1.

There is growing evidence that leptin regulation is altered in OSAS. Most studies reported on increased leptin levels in patients with OSA 95 , — , which were commonly correlated with an apnea-hypopnea index 95 , Furthermore, specific treatment of OSA with nasal CPAP resulted in decrease in leptin levels 95 , , It was suggested that hyperleptinemia may be a prognostic marker of OSA Because leptin levels are high in patients with OSA independent of body fat content, it was postulated that OSA is associated with resistance to the weight-reducing effects of leptin , which may in turn result in increased appetite and weight gain.

Another relatively recently discovered hormone that regulates appetite and body weight is ghrelin. In a recent study of patients with OSA and BMI-matched control subjects, ghrelin levels were shown to be significantly higher in patients with OSA CPAP treatment of 2 days was sufficient to significantly reduce ghrelin levels in these patients The appetite stimulating effects of ghrelin may well contribute to increased caloric intake and weight gain in patients with OSA.

Orexin also called hypocretin is also an additional appetite-stimulating neuropeptide. Hypocretin-1 and -2, or orexin-A and -B, are produced by lateral hypothalamic neurons and participate in the control of feeding, sleep, wakefulness, neuroendocrine homeostasis, and autonomic regulation.

Initially, a role in appetite control was suggested as the main action of the two hypothalamic neuropeptides, since their site of synthesis and incretion, the lateral hypothalamus, is primarily involved in the control of food ingestion.

Destruction of lateral hypothalamic areas results in underfeeding, and orexins were thought to be the substances mediating appetite-stimulating drives.

However, further studies indicate a more complex array of functions and effects While orexin levels are clearly important for vigilance and are low undetectable in somnolence disorders such as narcolepsy, in OSA, there are inconsistent reports. Studies reported both increased levels and reduced levels of orexin in OSA.

One study reported a positive correlation between an apnea-hypopnea index and orexin levels , which may potentially explain the tendency toward weight gain in patients with OSA. We have measured orexin in extremely sleepy patients after surgical removal of a craniopharyngioma tumor.

Although we expected to find low levels, which would explain the severe sleepiness, we found normal and even high levels, which would explain the constant increase in body weight we observed in our patients In summary, it appears that there are complex relationships between obesity and OSA, with many factors affecting both.

It is well established that obesity can result or worsen OSA, via several potential mechanisms. Whether OSA worsens obesity is less clear at this time, although there are several potential mechanisms that support such a sequence. Large-scale well-controlled studies may shed light on this complex subject.

Potential mechanisms formatting a vicious cycle where obesity may result in OSA and OSA may lead to weight gain see text for details. UAW, upper airway. A brief summary of most studies investigating the association of OSA with various hormones and the effects of treatment with CPAP.

This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and Hypertension CODHy. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care.

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Section III: Obesity-The Rising Epidemic February 01 Abdominal Fat and Sleep Apnea : The chicken or the egg? Giora Pillar, MD, PHD ; Giora Pillar, MD, PHD. This Site. Google Scholar. Naim Shehadeh, MD Naim Shehadeh, MD. Address correspondence and reprint requests to Giora Pillar, MD, PhD, Sleep Lab, Rambam Medical Center and Technion, Haifa , Israel.

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Figure 1—. View large Download slide. Table 1— A brief summary of most studies investigating the association of OSA with various hormones and the effects of treatment with CPAP. Effect on appetite. Level in OSA. Effect of CPAP. Insulin Decrease Increased insulin resistance Decrease Leptin Decrease Increased leptin resistance Decrease Ghrelin Increase Increased Decrease Orexin Increase Conflicting results Increase.

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Sleep Med. Pillar G, Peled R, Lavie P: Recurrence of sleep apnea without concomitant weight increase 7. Pillar G, Schnall R, Peled R, Lavie P: Surgical treatment of sleep apnea syndrome. Isr J Med Sci. Twenty-two million Americans suffer from sleep apnea, a serious health condition in which breathing repeatedly stops and starts, causing patients to wake up randomly throughout their sleep cycles.

The condition, which is usually marked by loud snoring, can increase your risk for high blood pressure and stroke. While obesity is the primary risk factor for developing sleep apnea, there are other causes, such as having large tonsils or a recessed jaw.

CPAP continuous positive airway pressure machines improves sleep apnea in about 75 percent of patients, studies suggest, but for the other 25 percent — those who may have trouble tolerating the machine — alternative treatment options, such as oral appliances or upper airway surgery, are more complicated.

A study led by Schwab compared obese patients with and without sleep apnea, and found that the participants with the condition had significantly larger tongues and a higher percentage of tongue fat when compared to those without sleep apnea.

The researchers' next step was to determine if reducing tongue fat would improve symptoms and to further examine cause and effect.

The new study included 67 participants with mild to severe obstructive sleep apnea who were obese —those with a body mass index greater than Through diet or weight loss surgery, the patients lost nearly 10 percent of their body weight, on average, over six months.

Before and after the weight loss intervention, the study participants underwent MRI scans to both their pharynx as well as their abdomens. Then, using a statistical analysis, the research team quantified changes between overall weight loss and reductions to the volumes of the upper airway structures to determine which structures led to the improvement in sleep apnea.

The team found that a reduction in tongue fat volume was the primary link between weight loss and sleep apnea improvement. The study also found that weight loss resulted in reduced pterygoid a jaw muscle that controls chewing and pharyngeal lateral wall muscles on the sides of the airway volumes.

Both these changes also improved sleep apnea, but not to the same extent as the reduction in tongue fat. The authors believe that tongue fat is a potential new therapeutic target for improving sleep apnea. They suggest that future studies could be designed to explore whether certain low-fat diets are better than others in reducing tongue fat and whether cold therapies — like those used to reduce stomach fat — might be applied to reducing tongue fat.

However, Schwab notes, these types of interventions have not yet been tested. In a recent related study , Schwab found that ethnicity may also play a role in sleep apnea severity.

His research team compared the upper airway anatomy of Chinese and Icelandic patients with sleep apnea, and found that, compared to Icelandic patients of similar age, gender, and symptoms, Chinese patients had smaller airways and soft tissues, but bigger soft palate volume with more bone restrictions.