Daytime Sleepiness in Obesity: Mechanisms Beyond Obstructive Sleep Apnea—A Review

DAYTIME SLEEPINESS IN OBESITY: MECHANISMS BEYOND OSA http://dx.doi.org/10.5665/sleep.1812 Daytime Sleepiness in Obesity: Mechanisms Beyond Obstructive Sleep Apnea—A Review Lori A. Panossian, MD; Sigrid C. Veasey, MD Center for Sleep and Circadian Neurobiology and Department of Medicine, Sleep Division, University of Pennsylvania, Philadelphia, PA Increasing numbers of overweight children and adults are presenting to sleep medicine clinics for evaluation and treatment of sleepiness. Sleepiness negatively affects quality of life, mental health, productivity, and safety. Thus, it is essential to comprehensively address all potential causes of sleepiness. While many obese individuals presenting with hypersomnolence will be diagnosed with obstructive sleep apnea and their sleepiness will improve with effective therapy for sleep apnea, a significant proportion of patients will continue to have hypersomnolence. Clinical studies demonstrate that obesity without sleep apnea is also associated with a higher prevalence of hypersomnolence and that bariatric surgery can markedly improve hypersomnolence before resolution of obstructive sleep apnea. High fat diet in both humans and animals is associated with hypersomnolence. This review critically examines the relationships between sleepiness, feeding, obesity, and sleep apnea and then discusses the hormonal, metabolic, and inflammatory mechanisms potentially contributing to hypersomnolence in obesity, independent of sleep apnea and other established causes of excessive daytime sleepiness. Keywords: Obstructive sleep apnea, obesity, hypersomnolence, neurons/metabolism, sleep/physiology Citation: Panossian LA; Veasey SC. Daytime sleepiness in obesity: mechanisms beyond obstructive sleep apnea—a review. SLEEP 2012;35(5):605-615. Excessive daytime sleepiness, obesity and obstructive sleep apnea (OSA) are all prevalent conditions in developed countries. Approximately 6% to 12% of the general population regularly experiences subjective sleepiness, as measured with the Epworth Sleepiness Scale.1-3 Approximately 60% of adults in many developed countries are overweight, defined as a body mass index (BMI) > 25 kg/m2, and one-third of adults are obese, defined as a BMI > 30 kg/m2.4 In severely obese individuals, defined by a body mass index > 35 kg/m2, the prevalence of excessive daytime sleepiness approximates 30%.5 Obesity is the largest risk factor for OSA. The overall prevalence of OSA in the general population is 2% to 4%,6 and in obese individuals the prevalence of OSA is 30%.7 Thus, it would seem that OSA alone could potentially explain the high prevalence of sleepiness observed in obese individuals. Despite the close association between obesity and OSA, studies repeatedly demonstrate weak relationships (r2 < 0.3) between the severity of OSA, as defined by the apnea-hypopnea index (AHI), and the severity of subjective sleepiness, as defined by the Epworth Sleepiness Scale.8-11 Moreover, many individuals with OSA continue to have some degree of sleepiness despite effective therapy for OSA. Some of this sleepiness may be the consequence of irreversible injury to wake neurons from OSA.12-15 But are we, as sleep clinicians, overlooking obesity and diet as possible contributors to sleepiness in obese patients? Residual Sleepiness in Treated Obstructive Sleep Apnea Upon therapy for OSA, most individuals can expect significant improvements in daytime sleepiness. Indeed, a strong dose-related improvement in sleepiness is observed with usage Submitted for publication September, 2011 Submitted in final revised form December, 2011 Accepted for publication December, 2011 Address correspondence to: Lori Panossian, University of Pennsylvania, Translational Research Bldg, 125 S. 31st St.; Tel: (215) 746-4801; Fax: (215) 746-4814; E-mail: SLEEP, Vol. 35, No. 5, 2012 605 hours of continuous positive airway pressure (CPAP) therapy.14,16 However, a significant proportion of people with moderate-to-severe OSA continue to experience excessive sleepiness, even after adequate treatment with CPAP. Prevalence rates vary and have been estimated at 12% to 30% among obese individuals using CPAP ≥ 4 h/night.14,17 Even with longer nightly treatment times, 30% of obese subjects (mean BMI = 35 kg/m2) using CPAP ≥ 7 h/night continue to have objective sleepiness measured by the maintenance of wakefulness test, and 20% of subjects have abnormal Epworth scores.14 Among CPAP users with a BMI > 30, some of the lasting sleepiness might be attributed to comorbid sleep disorders, depression, or sedating medications; for example, Pépin et al. found that prevalence rates of residual sleepiness dropped from 12% to 6% after adjusting for these factors.16,17 Nevertheless, given the high rates of both OSA and obesity, this relatively low percentage represents large numbers of the general population. Stradling has argued that the prevalence of sleepiness in patients treated for OSA is similar to the prevalence of sleepiness in the general population, both approximately 12%.18 But what are the causes of excessive daytime sleepiness in 12% of obese OSA patients and 6% to 12% of the general adult population, as well as up to 30% of severely obese patients? At present, there is insufficient evidence to attribute all persistent sleepiness in treated OSA patients to irreversible injury from OSA; thus, we need to explore the possibility of reversible causes of hypersomnolence. Effects of Bariatric Surgery on Wakefulness Overall, patients with OSA and excessive daytime sleepiness who undergo bariatric surgery can expect a dramatic improvement in subjective sleepiness.10,19,20 In a study of severely obese patients with OSA who underwent gastric bypass (n = 56), the Epworth sleepiness score for the group fell from 14 (severe sleepiness) preoperatively to 5 (normal) at one month after surgery, a time when weight loss is expected to be just 1012 pounds.21 OSA was not reassessed with polysomnography at the one-month interval, but it is unlikely that this amount of weight loss in severely obese individuals would correct OSA. Metabolic Regulation of Wakefulness—Panossian and Veasey OSA, dietary modification or surgery-induced negative energy balance, and through what molecular mechanisms does bariatric surgery improve wakefulness? BLOOD PANCREAS enterostatin STOMACH AND SMALL INTESTINE insulin glucose Leptin Ghrelin Peptide YY CCK ADIPOCYTES TNFα IL-6 Leptin Wakefulness Alertness Wake neuron signaling Orexin 5-HT Norepinephrine Sleepiness Sedation Figure 1—Gut hormones and adipokines with somnogenic effects. (Our example of pancakes with bacon and syrup is only one of many commonly ingested high fat, high sugar meals that could potentially induce the schematized gut and adipose somnogenic responses.) In response to ingestion of high fat, high sugar foods, the plasma carries increased glucose, insulin, leptin, cholecystokinin (CCK), peptide YY, and enterostatin, all of which ha (...truncated)