Hypoxia increases leptin expression in human PAZ6 adipose cells

Aims/hypothesis. Leptin, an adipose tissue-derived cytokine involved in the control of body weight, also participates in a variety of biological functions, including angiogenesis. Because reduced oxygen availability is a major inducer of angiogenesis, we hypothesized that low cellular oxygen tension could regulate leptin expression in adipose cells. Methods. Differentiated PAZ6 adipocytes were cultured for 48 h in the presence of chemical inducers of cellular hypoxia (cobalt chloride or desferrioxamine) or in an atmosphere containing only 6% oxygen. The effect of hypoxia on the expression of leptin and several adipose genes was assessed by semi-quantitative RTPCR. The effect of hypoxia on leptin promoter activity was tested in PAZ6 cells transiently transfected with a luciferase reporter construct, containing 1.87 kb of the human leptin promoter. Leptin secretion in the culture medium was determined by radioimmunoassay. Results. Hypoxia increased leptin mRNA expression, leptin promoter activity and leptin secretion in the culture medium by two- to threefold (p<0.05). The expression of the glucose transporter isoform 1 (GLUT-1) mRNA, a well known hypoxia inducible gene, was also increased. In contrast, glucose transporter isoform 4 (GLUT-4), hormone sensitive lipase (HSL), fatty acid binding protein (aP2) and uncoupling protein 2 (UCP2) mRNAs were markedly reduced by hypoxia. In addition, a similar hypoxia-induced increase in leptin mRNA and secretion was observed in primary rat adipose cells. Conclusion/interpretation. Hypoxia markedly and specifically increased leptin gene expression through activation of the leptin gene promoter, and this resulted in an increased leptin production by human PAZ6 adipocytes.