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withdrawn, the early up-regulation of Fra-1 results in inhibition of the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.