Endocrine Abstracts (2015) 38 P243 | DOI: 10.1530/endoabs.38.P243

Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of morbidly obese patients with hypoventilation syndrome and obstructive sleep apnoea syndrome but not in the moderately obese

Marijana Todorčević1, Luke Austen2, Ari Manuel3, Zoi Michailidou4, John Stradling3,5 & Fredrik Karpe1,5


1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 2Pembroke College, University of Oxford, Oxford, UK; 3Oxford Respiratory Trials Unit, Churchill Hospital, University of Oxford, Oxford, UK; 4Queen’s Medical Research, Institute Centre for Cardiovascular Research, University of Edinburgh, Edinburgh, UK; 5NIHR Oxford Biomedical Research Centre, OUH Trust, Churchill Hospital, Oxford, UK.


Adipose tissue (AT) dysfunction is thought to be a central component in the pathophysiology of obesity-associated metabolic disease. Low AT oxygenation (hypoxia) is suggested to be a driver of this dysfunction, yet studies in humans have resulted in conflicting data. Therefore, we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of morbidly obese individuals who had hypoxia from obesity hypoventilation syndrome (OHS), with or without obstructive sleep apnoea (OSA), two extreme phenotypes with the potential to produce a proof of principle type result.

To provide a methodological positive control for the detection of cellular makers of hypoxia in human AT, we undertook in vitro cellular studies in which human primary adipocytes were incubated in normoxic (21% O2; 5% CO2) or hypoxic (1% O2; 5% CO2) conditions. As expected, hypoxia significantly increased HIF1A protein in primary adipocytes and gene expression of both classical HIF1A target genes (GLUT1 and VEGFA) and hypoxia-sensitive pro-inflammatory genes (IL6 and PAI1). We then measured these markers in human subcutaneous AT from subjects of 4 distinct phenotypes: lean (BMI=24.2), moderately obese (BMI=32.5), morbidly obese with OHS (BMI=45.3) and morbidly obese with OHS and OSA (BMI=45.3).

We found no significant differences in either AT HIF1A protein levels or AT expression of hypoxia-sensitive genes between lean and moderately obese subjects. In contrast, subjects with either OHS, or OHS with OSA, exhibited significantly higher HIF1A protein levels versus moderately obese and lean controls (OHS fivefold compared to moderately obese; OHS with OSA sixfold compared to moderately obese), and this was correlated with expression of hypoxia-sensitive genes.

Our results suggest that markers of AT hypoxia only become evident in individuals with both extreme levels of adiposity and systemic hypoxia. In addition, there is an additive effect on hypoxia markers in patients with OSA over and above OHS alone. Although our data are not consistent with the view that AT hypoxia drives metabolic dysfunction in moderate obesity, AT hypoxia may contribute to the development of metabolic dysfunction in OHS and OSA.