Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis

The aryl-hydrocarbon receptor (AhR) is a ligand-dependent transcription fac tor that mediates the biological effects of 23,7,8-tetrachlorodibenzo-p-dio xin (TCDD), In mouse embryo fibroblasts, TCDD activates expression of multi ple genes, including CYP1B1, the predominant cytochrome P450 expressed in t hese cells. Here, we analyze constitutive functions of the AhR in primary m ouse embryo fibroblasts (MEFs) and spontaneously immortalized MEF cell line s derived from wild-type (WT) C57BL/6 mice and also from congenic mice with a targeted disruption of the AhR gene (AhR(-/-)). After multiple passages, primary MEFs exhibit spontaneous differentiation, growth cessation and sen escence. Eventually, colonies of immortalized MEFs arise to provide clonal lines. The senescent phase occurs much earlier for AhR(-/-) MEFs, while imm ortalization is substantially delayed. Comparison of AhR(-/-) and WT MEFs a lso indicates that constitutive AhR activity is required for basal expressi on of CYP1B1 and suppresses lipogenesis in subconfluent cultures. Primary W T and AhR(-/-) MEFs and the corresponding lines undergo adipogenesis when t reated at confluence with the appropriate hormonal inducers. Addition of TC DD before or concurrent with hormonal induction suppressed PPAR gamma mRNA and adipogenesis, as measured by lipid accumulation, glycerol phosphate deh ydrogenase activity and stearoyl CoA desaturase type 1 mRNA expression. Thi s effect of TCDD treatment was absent in AhR(-/-) MEFs, establishing the ro le of AhR in hormone-induced adipogenesis, Such hormonal activation of conf luent MEFs and preadipocytes results in a limited proliferative expansion f ollowed by irreversible growth arrest, TCDD-treated MEFs undergo the mitoti c expansion but fail to exit the cell cycle. In AhR(-/-) MEFs, there is no such effect of TCDD, These findings implicate the AhR as a constitutive inh ibitor of triglyceride synthesis, and as an early regulator of adipocyte di fferentiation. AhR interference with cell-cycle arrest in differentiation m ay be linked to the increased rate of senescence.