Prostaglandins Promote and Block Adipogenesis through Opposing Effects on Peroxisome Proliferator-activated Receptor γ

Mauricio J Reginato,Samuel L Krakow,Shannon T Bailey,Mitchell A Lazar

doi:10.1074/jbc.273.4.1855

Mauricio J Reginato, Samuel L Krakow + Show 2 more

Open Access

https://doi.org/10.1074/jbc.273.4.1855

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Abstract

Fat cell differentiation is a critical aspect of obesity and diabetes. Dietary fatty acids are converted to arachidonic acid, which serves as precursor of prostaglandins (PGs). PGJ2 derivatives function as activating ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor that is central to adipogenic determination. We report here that PGF2 alpha blocks adipogenesis through activation of mitogen-activated protein kinase, resulting in inhibitory phosphorylation of PPAR gamma. Both mitogen-activated protein kinase activation and PPAR gamma phosphorylation are required for the anti-adipogenic effects of PGF2 alpha. Thus, PG signals generated at a cell surface receptor regulate the program of gene expression required for adipogenesis by modulating the activity of a nuclear hormone receptor that is directly activated by other PG signals. The balance between PGF2 alpha and PGJ2 signaling may thus be central to the development of obesity and diabetes.

Highlights

The MAP kinase inhibitor PD98059 had little effect on its own. It completely prevented inhibition of adipogenesis by PGF2␣ and by fluprostenol, indicating that MAP kinase activation was required for the anti-adipogenic effects of these compounds. This effect of PD98059 was specific for inhibition by PGF2␣ and fluprostenol, because PD98059 had no effect on the ability of retinoic acid (RA) to inhibit adipogenesis, consistent with evidence that RA acts by antagonizing the effects of C/EBP [29], a mechanism that would be predicted to be independent of MAP kinase
PGF2␣ and PGJ2 derivatives are different products of AA metabolism with opposing biological effects mediated by cell surface and nuclear receptors, respectively
These converge on the PG nuclear receptor peroxisome proliferator-activated receptors (PPARs)␥ as in the model shown in Fig. 4. 3T3-L1 cells are known to produce PGF2␣, and in accordance with recent suggestions our model proposes that a PPAR␥ ligand related to PGJ2 is endogenously produced during adipogenesis

Summary

Introduction

The adipogenic effects of PGJ2 derivatives involve direct activation of nuclear PPAR␥, PGF2␣ utilizes a specific GPCR on the cell surface to initiate intracellular signal transduction [21,22,23,24]. We and others recently showed that activation of the MAP kinase pathway phosphorylates PPAR␥ and inhibits adipogenesis [25,26,27]. Insulin can induce phosphorylation of ectopic PPAR␥ in cells expressing ectopic insulin receptor [27], insulin is adipogenic, and its ability to activate MAP kinase does not play an important role during adipogenesis [28]. We show that PGF2␣ induces phosphorylation of PPAR␥ via activation of MAP kinase and that this is required for inhibition of 3T3-L1 adipogenesis by PGF2␣

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