Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea

Abstract

Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.Keywords: intermittent hypoxia; diabetes; insulin resistance; obstructive sleep apnea; lipolysis Clinical RelevanceThis study suggests that adipose tissue lipolysis represents a mechanism linking obstructive sleep apnea syndrome with glucose intolerance, insulin resistance, and type 2 diabetes in a mouse model. Furthermore, the study shows that pharmacological inhibition of lipolysis ameliorated detrimental metabolic effects induced by intermittent hypoxic exposure.Obstructive sleep apnea (OSA), with a prevalence of 5-15%, represents a common condition in the adult population (1). Repetitive partial or complete collapse of the upper airway during sleep results in periodic drops in blood oxygen levels (hypoxemia) and sleep fragmentation. Previous research has identified OSA as an independent risk factor for hypertension, cardiovascular diseases, stroke, and allcause mortality (2, 3). More recently, studies indicate that OSA is also associated with glucose intolerance, insulin resistance, and type 2 diabetes mellitus (T2DM), independently of other confounding Author Contributions: Conception and design-M.W., L.A.S., and J.P.; analysis and interpretation-M.W., L.A.S., M.K., O.S., and J.P.; drafting the manuscript for important intellectual content-M.W., L.A.S., and J.P.

Adipose tissue as a key player in obstructive sleep apnoea

“…https://doi.org/10.1183/16000617.0006-2019 responsible for the release of free fatty acids and glycerol, as a result of adipose tissue lipolysis by hormone sensitive lipase [37]. In rodents, IH exposure induces adipose tissue lipolysis, and pharmacological inhibition of lipolysis by acipimox prevents IH-induced insulin resistance in mice [25,29,38]. However, sympatholytic strategies using adrenergic blockade or adrenal medullectomy only abolish IH-induced lipolysis without a beneficial effect on peripheral insulin resistance [39][40][41], again supporting a more complex signalling pathway involving complementary mechanisms.…”

Sleep apnea: An overlooked cause of lipotoxicity?

“…In animal models of OSA, chronic intermittent hypoxia (IH) increased FFA, accelerated dyslipidemia and atherosclerosis in apolipoprotein E-deficient mice fed a high cholesterol diet [37]. IH also increased plasma FFA in mice, which was abolished by β blockade with propranolol [38] or a lipolysis inhibitor, acipimox [39]. Likewise, SNS-mediated lipolysis occurs during high altitude hypoxia in healthy humans [40].…”

“…Weiszenstein et al . showed that chronic IH-induced IR could be prevented by administering the lipolysis inhibitor, acipimox [39]. Diabetes-prone Tallyho/JngJ (TH) mice exposed to IH exhibited pancreatic β-cell apoptosis and dysfunction, in association with increased FFA levels in plasma and pancreatic tissue [11].…”

Adipose tissue inflammation by intermittent hypoxia: mechanistic link between obstructive sleep apnoea and metabolic dysfunction

“…; Weiszenstein et al . ). Pharmacological inhibition of lipolysis by acipimox, a nicotinic acid analogue, ameliorated the detrimental effects on glucose metabolism induced by chronic IH exposure (Weiszenstein et al .…”

“…Pharmacological inhibition of lipolysis by acipimox, a nicotinic acid analogue, ameliorated the detrimental effects on glucose metabolism induced by chronic IH exposure (Weiszenstein et al . ) and in a recent investigation using a combined in vivo–in vitro approach a potential mechanistic link between IH and lipolysis was proposed through upregulation of endothelin 1 (ET‐1) (Briancon‐Marjollet et al . ).…”