Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension

Adipose tissue becomes hypoxic in obesity, and cell culture studies have demonstrated that hypoxia leads to major changes in adipocyte function. Studies on the response of adipocytes to low O-2 tension have employed marked hypoxia (1% O-2). Here, we have examined the effects of modest hypoxia, utilising differing concentrations of O-2 (1-21%), on adipokine production and glucose uptake by human adipocytes. Incubation with 10% O-2 (24 h) increased expression of the leptin, vascular endothelial growth factor (VEGF) and Angptl4 genes, while leptin expression was elevated even at 15% O-2 (compared to 'normoxia'aEuro21% O-2). Overall, there was a concentration-dependent increase in the expression of these genes as O-2 fell, with the highest mRNA level evident at 1% O-2. Parallel changes were observed in the secretion of leptin, VEGF and IL-6 into the medium, an increased release being evident at 10% O-2 (15% O-2 for leptin). Adiponectin gene expression was reduced at 15% O-2 and below, while adiponectin release was significantly reduced at 5% O-2. Both 2-deoxy-d-glucose uptake and lactate release showed progressive increases as O-2 concentration fell, being significantly raised at 10% and 5% O-2, respectively. The alterations in substrate transport were accompanied by parallel changes in transporter gene expression, GLUT1 and MCT1 mRNA level increasing from 15% and 10% O-2, respectively. These results indicate that marked responses to reduced O-2 concentration are exhibited by human adipocytes at O-2 levels well above those associated with hypoxia and employed in cell culture studies. Adipocytes are sensitive to small changes in O-2 tension.