Dietary fat has been correlated with obesity since it induces the proliferation and differentiation of pre-adipocytes. Now it has become clear that the effect of fat on human health depends on the composition and the nature of fatty acids. Arachidonic acid (AA) is a major omega-6 polyunsaturated fatty acid (PUFA) with a controversial role in adipocyte differentiation. We investigated the effect on pre-adipocyte differentiation after a brief exposure to AA.
We show that a short treatment of 3T3-L1 cells with AA at the start of differentiation induces events with a long lasting inhibitory effect on adipogenesis. Treatment of pre-adipocytes with AA for only 24 h prevented differentiation since the expression of adipocyte markers (PPARγ, c/EBPα etc.) and lipid accumulation were significantly reduced after 10 days of differentiation.
In addition, after 24 h of differentiation in the presence of AA treatment the fatty-acid binding protein 4 (FABP4 or aP2) expression was induced 100-fold. We show that this effect is PPARγ-dependent since AA treatment was unable to induce aP2 upregulation in PPARγ knockdown cells. This appears to be a gene-specific event as other PPARγ targets were not affected by AA. Treatment with indomethacin, a general cycloxygenase inhibitor, blocked AA action on aP2 expression indicating that this effect is prostaglandin-mediated.
We suggest that a short treatment with AA during the early stages of adipocyte differentiation regulates PPARγ expression and/or activity with two very different outcomes. On the one hand, PPARγ in the presence of AA causes the rapid early upregulation of its primary target aP2. On the other hand, at the later stages of differentiation in the absence of AA, PPARγ expression fails to be induced and initiate the differentiation program.