Megestrol acetate-induced differentiation of 3T3-L1 adipocytes in vitro

We recently observed significant weight gain in patients with advanced breast cancer treated with high-dose megestrol acetate. However, the mechanisms of this effect are completely unknown. As the analysis of the action of steroids in vivo is complex, we chose to examine the effects of megestrol acetate on the differentiation of a preadipocyte clone (L1) of the Swiss 3T3 mouse fibroblast cell line. Addition of insulin, fetal bovine serum, dexamethasone, and methyl-isobutylxanthine to confluent 3T3-L1 cells induced adipocyte differentiation, as verified by morphologic studies and analysis of the activity of the enzyme glycerol-3-phosphate dehydrogenase (G-3-PD), a specific and sensitive indicator of lipocyte function. Substitution of megestrol acetate for dexamethasone also resulted in greatly increased lipocyte differentiation. Tumor necrosis factor (TNF) alpha blocked the adipocyte differentiation induced by the combination of insulin, dexamethasone, and methyl-isobutylxanthine. Addition of megestrol acetate failed to reverse the inhibitory effect of TNF. Thus, megestrol acetate, in vitro, is a potent inducer of lipocyte differentiation. Further studies on the regulation of adipocyte differentiation and function in this model system may be important to clarify megestrol acetate's mechanism of action.