Background/Aims: Hypoxia occurs in white adipose tissue in obesity, modulating the expression and release of specific inflammation-related adipokines. ANGPTL4 (angiopoietin-like protein 4/fasting-induced adipose factor), which is implicated in angiogenesis, lipid metabolism and glucose homeostasis, is a major hypoxia-sensitive gene; recent studies indicate that ANGPTL4 expression is also regulated by fatty acids. We have examined the effects of hypoxia and fatty acids, alone and together, on the expression and release of ANGPTL4 by human adipocytes. Methods: Human adipocytes were differentiated and incubated with fatty acids (250 mu M) in normoxia (21% O(2)) or hypoxia (1% O(2)). ANGPTL4 mRNA was measured by real-time PCR and the protein in the medium determined by ELISA. Results: In normoxia, ANGPTL4 gene expression was upregulated by palmitic, oleic, arachidonic and eicosapentaenoic acids, and ANGPTL4 release was increased. In contrast, there was no effect of lauric or myristic acids. Hypoxia alone increased the expression and secretion of ANGPTL4, and lauric, myristic, arachidonic and eicosapentaenoic acids each further increased expression and release in hypoxic adipocytes. Conclusion: The expression and secretion of ANGPTL4 by human adipocytes is upregulated by both hypoxia and fatty acids. The stimulatory effect of fatty acids on ANGPTL4 production is augmented under hypoxic conditions.