Adipose tissue transcriptomes in obstructive sleep apnea: location matters.

Obstructive sleep apnea (OSA) is a male-preponderant disorder associated with impaired neurocognitive performance, including sleepiness, mistakes, accidents, and reduced productivity; cardiometabolic dysfunction such as obesity and type 2 diabetes mellitus; and disorders of mixed etiology such as erectile dysfunction in men [1]. Whereas randomized controlled trials show that continuous positive airway pressure (CPAP) improves some measures of neurocognitive performance [2], cardiometabolic outcomes are not improved [3–5] except in those who adhere to CPAP [4, 5]. An important consideration is that studies that aim to determine the effectiveness of a therapy to be applied in the community require an intention to treat analysis, whereas restricting the study cohort to adherent participants in a perprotocol analysis is appropriate if the goal is to understand mechanistic pathways. In this regard, the combination of CPAP with weight loss is no better than weight loss alone in adherent participants for some cardiometabolic endpoints, including circulating C-reactive protein [6], raising the possibility that some of the cardiometabolic associations of OSA may simply be coincident with obesity. For these reasons, the study by Gharib et al in this issue of the journal is a welcome addition to the scientific literature [7]. It examines for the first time the transcriptome of subcutaneous adipose tissue in 10 adults with moderate untreated OSA compared with 8 controls without OSA who were similar by age, body mass index (BMI), and gender and were undergoing ventral hernia repair (study 1). Additionally, the transcriptome of subcutaneous adipose tissue obtained before and after an average of 44 nights of adherent (>6 h/night) CPAP therapy was also investigated in a separate cohort of 24 adults with severe OSA (study 2). Gharib et al examined subcutaneous fat because it can be repetitively sampled using a simple procedure that can be performed outside the operating room. However, not all fat is the same. Epidemiological data strongly implicate visceral, rather than subcutaneous, adiposity with cardiometabolic risk, particularly with insulin resistance which is a key factor in the development of prediabetes and type 2 diabetes mellitus—diseases which affect over 100 million Americans at an annual cost that exceeds $200 billion [8]. These differences in risk occur in part because the endocrine function of adipose tissue differs quantitatively between visceral and subcutaneous fat: visceral fat secretes more hormones that induce insulin resistance such as cortisol (due to higher 11β-hydroxysteroid dehydrogenase-1 which converts inactive cortisone to cortisol) and proinflammatory cytokines (such as TNF-α and IL-6), but less hormones that improve insulin sensitivity, such as leptin and adiponectin [9, 10]. The effects of these secretions also differ substantially because visceral fat hormones enter the portal circulation where they can directly alter lipid, carbohydrate, and protein metabolism by the liver, whereas subcutaneous fat hormones enter the systemic circulation. There are also substantial differences in the distribution of body fat between men and women, where men tend to accumulate more abdominal and visceral body fat (android obesity) compared with females, who tend to accumulate more adipose tissue on hips and thighs (gynoid obesity). Androgens and estrogens are known to dictate these differences in fat distribution, and other researchers are unveiling the transcriptomic and epigenomic effects of these sex hormones on fat, muscle, and skin [11]. Although OSA is a male-preponderant disorder, 78% (study 1) and 46% (study 2) of the participants studied by Gharib et al were females [7]. Whether the differences in overall body fat distribution, sex hormone milieu, and gender impact generalizability to men with OSA warrants further investigation. SLEEPJ, 2020, 1–3