Progesterone stimulates adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c gene expression - Potential mechanism for the lipogenic effect of progesterone in adipose tissue

Fatty acid synthase (FAS), a nutritionally regulated lipogenic enzyme, is t ranscriptionally controlled by ADD1/SREBP1c (adipocyte determination and di fferentiation 1/sterol regulatory element-binding protein 1c), through insu lin-mediated stimulation of ADD1/SREBP1c expression. Progesterone exerts li pogenic effects on adipocytes, and FAS is highly induced in breast tumor ce ll lines upon progesterone treatment. We show here that progesterone up-reg ulates ADD1/SREBP1c expression in the MCF7 breast cancer cell line and the primary cultured preadipocyte from rat parametrial adipose tissue. In MCF7, progesterone induced ADD1/SREBP1c and Meta-Ilothionein II (a well known pr ogesterone-regulated gene) mRNAs, with comparable potency, In preadipocytes , progesterone increased ADD1/SREBP1c mRNA dose-dependently, but not SREBP1 a or SREBP2, Run-on experiments demonstrated that progesterone action on AD D1/SREBP1c was primarily at the transcriptional level. The membrane-bound a nd mature nuclear forms of ADD1/SREBP1 protein accumulated in preadipocytes cultured with progesterone, and FAS induction could be abolished by adenov irus-mediated overexpression of a dominant negative form of ADD1/SREBP1 in these cells, Finally, in the presence of insulin, progesterone was unable t o up-regulate ADD1/SREBP1c mRNA in preadipocytes, whereas its effect was re stored after 24 h of insulin deprivation, Together these results demonstrat e that ADD1/SREBP1c is controlled by progesterone, which, like insulin, act s by increasing ADD1/SREBP1c gene transcription, This provides a potential mechanism for the lipogenic actions of progesterone on adipose tissue.