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

• Main Author: Nikolopoulou, Evanthia
• Format: Dissertation
• Language: English
• Published: Imperial College London 2013
• DOI: 10.25560/14632

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 In the later stages of differentiation, when AA is withdrawn, the early up-regulation of Fra-1 results in inhibition of the differentiation program.