Obstructive sleep apnoea (OSA) represents a worldwide major health burden and conveys a significant risk for cardiometabolic diseases including insulin resistance or Type 2 diabetes. The pathogenesis underlying metabolic dysfunction in OSA remains poorly understood but intermittent hypoxia (IH)-induced adipose tissue (AT) inflammation with macrophage polarization towards a M1, pro-inflammatory phenotype likely plays a key role. Continuous positive airway pressure (CPAP) is the mainstay treatment for OSA but benefits on metabolic function are limited and consequently, alternative treatment strategies are urgently required. Weight loss in addition to CPAP is a promising approach but difficult to achieve with conventional measures alone. We hypothesize that a greater understanding of the pathophysiological pathways mediating IH-induced AT inflammation and metabolic dysfunction will lead to the identification of novel therapeutic approaches for OSA.
We will test the hypothesis in a truly bench-to bedside project through 3 inter-related aims:
Firstly, we aim to identify the signalling pathways driving IH-mediated macrophage M1-polarization and subsequent insulin resistance in cultured adipocytes using our state-of-the-art in vitro model of IH.
Next, we will extrapolate the results obtained in vitro to an extensively validated lean and diet-induced obese murine model of IH to determine relevant pathways mediating IH-induced AT dysfunction in vivo.
Finally, we will determine the potential therapeutic role of glucagon-like peptide (GLP)-1 receptor agonist, which is known to reduce AT inflammation and body weight, in IH-induced metabolic dysfunction in vitro, in vivo, in a human model of IH and in patients with OSA.
The successful completion of this project will identify the detailed mechanisms underlying IH-induced AT inflammation and metabolic dysfunction and will test the utility of a novel treatment strategy targeting this response and thus, should lead towards personalized therapeutic approaches for patients with OSA.
