Guggulsterone (GS) and 1,25-dihydroxyvitamin D3[1,25(OH)(2)D-3] have been shown to influence adipogenesis in 3T3-L1 cells. We investigated the ability of GS and 1,25(OH)(2)D-3, alone and in combination to inhibit adipogenesis and induce apoptosis in 3T3-L1 adipocytes. Maturing preadipocytes were treated with 1,25(OH)(2)D-3 in combination with GS for 6 days during differentiation. GS and 1,25(OH)(2)D-3 each inhibited lipid accumulation, but the combination potentiated the inhibition of lipid accumulation. Apoptosis was increased by 1,25(OH)(2)D-3 while GS had no effect, but GS + 1,25(OH)(2)D-3 increased apoptosis more than either compound alone. Furthermore, GS + 1,25(OH)(2)D-3 caused a potentiated decrease in the expression of aP2 and farnesoid X receptor expression more than either compound alone. In addition, 1,25(OH)(2)D-3 increased vitamin D receptor expression after 6 days, while GS had no effect. GS + 1,25(OH)(2)D-3, however, caused a potentiated increase in the expression of VDR. These findings show that GS potentiates 1,25(OH)(2)D-3's anti-adipogenic and pro-apoptotic effects in maturing 3T3-L1 preadipocytes. (C) 2007 Elsevier Inc. All rights reserved.