The effect of arachidonic acid on the early and late stages of adipocyte differentiation

Abstract

Dietary fat has been correlated with obesity since it induces the proliferation and differentiation of pre-adipocytes. However 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. Its role in adipocyte differentiation is controversial as published data have shown opposing roles of AA in pre-adipocyte differentiation. We investigated the effect of a brief exposure of AA on pre-adipocyte differentiation. After a 24h of AA treatment during pre-adipocyte differentiation, the expression of aP2, a differentiation marker, and Fra-1, an AP-1 transcription factor, was induced. We showed that this effect was PPARγ-dependent since AA treatment was unable to up-regulate aP2 and Fra-1 in PPARγ knockdown cells. Furthermore, we identified that both of these genes were regulated by the AA metabolite, PGF2α, through binding to its cognate GPCR, the FP receptor, initiating a cascade of signalling pathways involving PKC and ERK activation. We also showed that short-term treatment of pre-adipocytes with AA at the beginning of differentiation induced events with a long-lasting inhibitory effect on adipogenesis. Treatment of pre-adipocytes with AA for only 24h, blocked adipogenesis as revealed by significantly reduced expression of adipocyte markers and lipid accumulation after 10 days of differentiation. We demonstrated that Fra-1 mediated the inhibitory effect of AA, as Fra-1 depletion rescued the inhibition of differentiation by AA. We suggest that short-term exposure of pre-adipocytes to AA at the early stages of differentiation has a dual effect. In the early stages, the presence of AA causes a rapid up-regulation in two target genes, the aP2 and Fra-1, in a PPARγ-dependent way. In the later stages of differentiation, when AA is withdrawn, the early up-regulation of Fra-1 results in inhibition of the differentiation program.