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

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 ␥ (PPAR␥), a nuclear hormone receptor that is central to adipogenic determination. We report here that PGF2␣ blocks adipogenesis through activation of mitogen-activated protein kinase, resulting in inhibitory phosphorylation of PPAR␥. Both mitogen-activated protein kinase activation and PPAR␥ phosphorylation are required for the anti-adipogenic effects of PGF2␣. 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␣ and PGJ2 signaling may thus be central to the development of obesity and diabetes.Altered levels of free fatty acids or their metabolites commonly occur in obesity and diabetes (1, 2), and fatty acid uptake is increased in these disorders (3). Levels of arachidonic acid (AA), 1 which is derived from dietary essential fatty acids, are high relative to other fatty acids in obesity and diabetic states (4), and high levels of AA may exacerbate diabetes by negatively regulating glucose uptake (5). AA serves as precursor for eicosanoid signaling molecules including leukotrienes, hydroxyeicosatetraenoic acids, and prostaglandins (PGs) (6). Many eicosanoids signal via cell surface G-protein-coupled receptors (GPCRs) (7). Others including 8 S hydroxyeicosatetraenoic acids, leukotriene B4, and a number of PGs including PGJ2 and derivatives such as 15-deoxy-⌬12,14-PGJ2 (15d-PGJ2) bind and activate members of the nuclear hormone receptor superfamily (8) called peroxisome proliferator-activated receptors (PPARs) ␣ and ␥ (9 -12).Obesity is due to increased size and number of adipocytes. PPAR␥, the nuclear receptor for PGJ2 derivatives, plays a central role in adipogenesis (12)(13)(14). PPAR␥ is the target of thiazolidinediones, an exciting new class of antidiabetic drugs that function as direct ligands for PPAR␥ and have also been shown to be adipogenic (10,(15)(16)(17). An endogenous PPAR␥ ligand is therefore likely to be an important metabolic regulator.The rate-limiting step in PGJ2 biosynthesis is catalyzed by cyclooxygenase (COX) (18). The actions of different enzymes upon the COX product PGH2 lead to numerous PGs that have different effects on growth, differentiation, and function of many tissues, including PGF2␣ (7). PGF2␣ is known to be synthesized by preadipocytes but does not activate PPAR␥ (9) and by contrast has a potent inhibitory effect upon adipocyte differentiation (19,20). Thus, products of AA metabolism downstream of COX have opposing effects upon adipogenesis. Although 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...

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

“…Indeed, a previous report has specifically implicated a role for the MAPK signaling pathway in mediating the anti-adipogenic effects of PGF2a on 3T3-L1 preadipocytes by directly phosphorylating PPARg and inhibiting its transcriptional activity [Reginato et al, 1998]. However, we could find no evidence that Fig.…”

“…In contrast, a wide array of growth factors, cytokines, and other endocrine products, including epidermal growth factor, transforming growth factor-b, Wnt-10b, PREF-1, resistin, and the pro-inflammatory cytokines tumor necrosis factor-a, interleukin-6 and interleukin-1, have all been shown to potently inhibit adipogenesis [MacDougald and Mandrup, 2002]. Another class of products known to influence adipocyte differentiation is the prostaglandins [Serrero et al, 1992;Lepak and Serrero, 1993;Forman et al, 1995;Casimir et al, 1996;Reginato et al, 1998;Aubert et al, 2000]. The prostaglandins are a diverse class of structurally distinct metabolic products of arachidonic acid that are generated via the concerted actions of cyclooxygenases and other subsequent synthetic enzymes [Vane et al, 1998].…”

“…Specific prostaglandins have been shown to play distinct and opposing roles in the regulation of adipocyte differentiation. Thus, prostaglandins such as prostacyclin (PGI2) and PGJ2 are known to positively influence adipogenesis [Forman et al, 1995;Reginato et al, 1998;Aubert et al, 2000], whereas other prostaglandins such as PGF2a have been shown to be potent inhibitors of adipocyte differentiation [Serrero et al, 1992;Lepak and Serrero, 1993;Casimir et al, 1996].…”

An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies

“…In addition, the prostaglandin F synthase activity of AKR1C3 will alter signaling pathways and stimulate the proliferation of both hormone-dependent and hormoneindependent cancers. The PGF 2 isomers will stimulate the Gq-coupled F prostanoid receptor and activate signal cascades associated with proliferation and the inhibition of differentiation [11][12][13]. Reduction of PGD 2 levels by AKR1C3 will prevent its dehydration and rearrangement to form the J-series prostaglandins.…”

“…Of its endogenously relevant substrates, AKR1C3 has the highest catalytic activity for the reduction of PGD 2 [9;10]. The PGF 2 isomers will activate the Gq-coupled F-prostanoid receptor and initiate protein kinase C and MAPK signaling cascades that stimulate proliferation through mechanisms that include inhibition of the peroxisome proliferator-activated receptor γ (PPARγ) and activation of NF-κB [11][12][13][14]. The AKR1C3-mediated depletion of PGD 2 will also prevent the formation of anti-proliferative PGJ 2 isomers, including 15-deoxy-Δ12,14-PGJ 2 , which are natural PPARγ ligands and inhibitors of NF-κB signaling [15][16][17][18].…”