We studied the effect of endothelin-1 (ET-1) on the differentiation of adipocyte precursor cells obtained from human adipose tissue and cultured in a serum-free hormone-supplemented medium. ET-1 was found to inhibit in a dose-dependent manner the accumulation of lipid droplets and the expression of glycerol-3-phosphate dehydrogenase (GPDH), a marker of adipose differentiation. The half-maximal inhibitory effect was observed in the range of 8.5 x 10(-10) mol/L. Full inhibition required the continuous exposure of the cells to ET-1. The prevention of adipose conversion was not associated with a stimulation of mitogenesis. The presence of staurosporine, an inhibitor of the protein kinase C signaling pathway, completely prevented the inhibitory effect of ET-1 on adipose differentiation. Addition of ET-1 to newly developed fat cells also caused a suppression of GPDH activity without changing adipocyte morphology. Again, the magnitude of this effect was dependent on the exposure time. These findings suggest that ET-1 is a potent modulator of fat cell formation in man, which may act through activation of protein kinase C. Because of the close spatial relationship between fat cell precursors and blood vessels, ET-1 may exert its action in a paracrine manner.