TCDD administration after the pro-adipogenic differentiation stimulus inhibits PPARγ through a MEK-dependent process but less effectively suppresses adipogenesis


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Abstract

Hormone (IDMB)-induced adipogenesis in C3H10T1/2 cells is suppressed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the aryl hydrocarbon receptor (AhR). We have previously reported that TCDD addition 48 h before the hormonal stimulation of IDMB suppresses a key mediator of adipogenesis, the peroxisome proliferator-activated receptor (PPARγ), by a MEK/ERK dependent mechanism. Here we add to previous evidence that this synergism functions after IDMB addition but before increased PPARγ1 transcription. Suppression remains effective and MEK/ERK dependent when TCDD is added 6–12 h after IDMB addition but not when delayed to 16–24 h, thus preceding the rise in PPARγ mRNA. TCDD suppression of the number of committed adipocytes and of triglyceride formation is less effective with the delayed addition. TCDD therefore does not directly suppress the expression of the key mediator PPARγ1. An alternative mediation of adipocyte commitment is apparently less sensitive to the 6–12 h of delayed TCDD addition. TCDD suppression potencies (EC50 = 50 pM) match the potencies for stimulation of CYP1B1 protein and AhR-sensitive reporters. The AhR antagonist 3′-methoxy-4′-nitroflavone (3-MNF) inhibited both TCDD-mediated CYP1B1 induction and inhibition of PPARγ protein expression. This antagonism was only effective when 3-MNF was present in the 24-h period after IDMB addition. TCDD activation of AhR in conjunction with MEK/ERK therefore generates PPARγ1 suppression activity before the increase of PPARγ1 synthesis. The potency and inhibition data are consistent with induction of one or more gene products that sustain suppression through the extended period of PPARγ1 transcription.

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