Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential

Evanthia Nikolopoulou,Georgia Papacleovoulou,Frederic Jean-Alphonse,Giulia Grimaldi,Malcolm G Parker,Aylin C Hanyaloglu,Mark Christian

doi:10.1194/jlr.m049551

Evanthia Nikolopoulou, Georgia Papacleovoulou + Show 5 more

Open Access

https://doi.org/10.1194/jlr.m049551

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Abstract

Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. We examined the effect of a short exposure to AA at different stages of 3T3-L1 adipocyte differentiation. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F2α (PGF2α), as inhibition of cyclooxygenases or PGF2α receptor signaling counteracted the AA-mediated aP2 induction. In addition, calcium, protein kinase C, and ERK are all key elements of the pathway through which AA induces the expression of aP2. We also show that treatment with AA during the first 24 h of differentiation upregulates the expression of the transcription factor Fos-related antigen 1 (Fra-1) via the same pathway. Finally, treatment with AA for 24 h at the beginning of the adipocyte differentiation is sufficient to inhibit the late stages of adipogenesis through a Fra-1-dependent pathway, as Fra-1 knockdown rescued adipogenesis. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis.

Highlights

Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis
We demonstrate that AA, after 24 h of treatment, is metabolized by COXs to generate PGF2␣, which binds to its membrane G protein-coupled receptor (GPCR), the FP receptor, and in turn induces the calcium/protein kinase C (PKC)/ ERK signaling pathway that causes the upregulation of aP2 and Fos-related antigen 1 (Fra-1) expression
The results in this study reveal a new mechanism by which AA regulates gene expression early in adipogenesis that directs terminal differentiation

Summary

Introduction

Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F2␣ (PGF2␣), as inhibition of cyclooxygenases or PGF2␣ receptor signaling counteracted the AA-mediated aP2 induction. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis.— Nikolopoulou, E., G. Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential. Adipocytes are the primary site for fat storage with 90% of the adipocytes’ cytoplasm containing a large lipid droplet [1]. Prostaglandins (PGs), the products of AA generated by cyclooxygenases (COXs), have opposing effects on adipogenesis, as prostacyclin (PGI2) and 15-deoxy-⌬12,14 prostaglandin J2 (PGJ2) promote [12,13,14,15] and prostaglandin E2 (PGE2) and prostaglandin F2␣ (PGF2␣) inhibit adipocyte differentiation [16,17,18]

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