Hypoxia modulates the expression and secretion of inflammation-related adipokines in differentiated human adipocytes

BACKGROUND: Obesity is characterised by a state of chronic low-grade inflammation. Recently, we proposed that hypoxia may occur in enlarged adipocytes distant from the vasculature as adipose tissue mass expands, and that this drives the inflammatory response through dysregulation of inflammation-related adipokines. We have now examined the effects of low oxygen tension and chemically induced hypoxia on the production of key adipokines in differentiated human adipocytes. METHODS: Cultured human adipocytes (15 days post differentiation) were exposed to 1% oxygen or 100 μM cobalt(II) chloride for up to 24 h; control cells were maintained in normal levels of oxygen only. mRNA levels of key adipokines were quantified by real-time PCR. Cellular levels of the hypoxia-sensitive transcription factor HIF-1α and the secretion of adipokines into the medium were measured with ELISAs. FINDINGS: A large (7·8 fold) increase in HIF-1α protein was induced in human adipocytes after 4 h of hypoxia. The mRNA level of the facilitative glucose transporter, GLUT1, increased 14 fold by 24 h and there were increases (by 24 h) in the level of the mRNAs encoding major adipokines, including leptin (28 fold), fasting-induced adipose factor (11 fold), vascular endothelial growth factor (23 fold), interleukin 6 (4·5 fold), and migration inhibitory factor (2·5 fold). By contrast, adiponectin mRNA level fell (3 fold). Changes in mRNA level were accompanied by parallel alterations in adipokine secretion into the medium. Similar results were obtained when hypoxia was induced chemically with cobalt(II) chloride. INTERPRETATION: Hypoxia dysregulates the production of key adipokines in human adipocytes, leading to an inflammatory state. Hypoxia may underlie the development of inflammation in adipose tissue in obesity. FUNDING: None.