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Title: Retinoid X Receptor Activation During Adipogenesis of Female Mesenchymal Stem Cells Programs a Dysfunctional Adipocyte.

Authors: Shoucri, Bassem M; Hung, Victor T; Chamorro-García, Raquel; Shioda, Toshi; Blumberg, Bruce

Published In Endocrinology, (2018 Aug 01)

Abstract: Early life exposure to endocrine-disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor (PPAR) γ and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ vs RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators ("rexinoids," 4204 and TBT) attenuate glucose uptake, blunt expression of the antidiabetic hormone adiponectin, and fail to downregulate proinflammatory and profibrotic transcripts, as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.

PubMed ID: 29860300 Exiting the NIEHS site

MeSH Terms: Adipocytes/cytology; Adipocytes/drug effects*; Adipogenesis/drug effects*; Adipose Tissue, White; Animals; Cell Differentiation/drug effects; Cyclopropanes/pharmacology*; Endocrine Disruptors/pharmacology*; Female; Hypoglycemic Agents/pharmacology; Mesenchymal Stem Cells/cytology; Mesenchymal Stem Cells/drug effects*; Mice; PPAR gamma/agonists; Retinoid X Receptors/agonists*; Rosiglitazone/pharmacology; Trialkyltin Compounds/pharmacology*

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