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Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo.

ABSTRACT: Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression. Here, using in vivo and in vitro models, we tested the hypothesis that TPhP is a selective PPARγ ligand, which fails to induce brite adipogenesis. C57BL/6 J male mice were fed either a low or very high-fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Compared to Rosi, TPhP did not induce expression of browning-related genes (e.g. Elovl3, Cidea, Acaa2, CoxIV) in mature adipocytes isolated from inguinal adipose. To determine if this resulted from an effect directly on the adipocytes, 3T3-L1 cells and primary human preadipocytes were differentiated into adipocytes in the presence of Rosi or TPhP. Rosi, but not TPhP, induced expression of brite adipocyte genes, mitochondrial biogenesis and cellular respiration. Further, Rosi and TPhP-induced distinct proteomes and phosphoproteomes; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. We assessed the role of phosphorylation of PPARγ in these differences in 3T3-L1 cells. Only Rosi protected PPARγ from phosphorylation at Ser273. TPhP gained the ability to stimulate brite adipocyte gene expression in the presence of the CDK5 inhibitor and in 3T3-L1 cells expressing alanine at position 273. We conclude that TPhP is a selective PPARγ modulator that fails to protect PPARγ from phosphorylation at ser273.

SUBMITTER: Kim S

PROVIDER: S-EPMC7443879 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Firemaster® 550 (FM550) is a chemical mixture currently used as an additive flame retardant in commercial products, and is comprised of 2-ethylhexyl-2,3,4,5-tertrabromobenzoate (TBB), bis(2-ethylhexyl) tetrabromophthalate (TBPH), triphenyl phosphate (TPP), and isopropylated triphenyl phosphate (IPTP). Animal and in vitro studies suggest that FM550, TPP and IPTP may have adipogenic effects and may exert these effects through PPARγ activation. Using murine 3T3-L1 preadipocytes, we investigated the detailed expression of transcription factors and adipogenic markers in response to FM550 and its components. Further we investigated the mechanism of action of the peroxisome proliferator-activated receptor gamma (PPARγ) on downstream targets of the receptor by focussing on the mature adipocyte marker, adipocyte protein 2 (aP2). In addition, we set to elucidate the components responsible for the adipogenic effects seen in the FM550 mixture. We show that FM550 and its components TPP, IPTP, and TBPH, but not TBB induced lipid accumulation in a dose-dependent manner. Interestingly, despite displaying enhanced lipid accumulation, TBPH did not alter the mRNA or protein expression of terminal differentiation markers. In contrast, FM550, TPP, and IPTP treatment enhanced lipid accumulation, and mRNA and protein expression of terminal differentiation markers. To further delineate the mechanisms of action of FM550 and its components we focussed on aP2 promoter activity. For this purpose we used the enhancer region of the mouse aP2 promoter using a 584-bp reporter construct containing an active PPRE located 5.4 kb away from the transcription start site of aP2. Exposure to FM550, IPTP, and TPP significantly increased PPARγ mediated aP2 enhancer activity. Furthermore, we show that TPP- and IPTP-dependent upregulation of aP2 was significantly inhibited by the selective PPARγ antagonist GW9662. In addition, chromatin immunoprecipitation experiments showed that IPTP and TPP treatment led to the recruitment of PPARγ to the regulatory region of aP2.

Project description:Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of toxicants is likely, albeit at low doses, the fact that multiple toxicants are capable of suppressing bone formation supports the hypothesis that environmental PPARγ ligands represent an emerging threat to human bone health.

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Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo.

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