GSE115946
Retinoid X receptor activation during adipogenesis of female mesenchymal stem cells programs a dysfunctional adipocyte
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?) 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 PPAR?. This led us to consider the functional consequences of PPAR? versus RXR activation in developing adipocytes. We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPAR? 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 anti-diabetic hormone adiponectin, and fail to down-regulate pro-inflammatory and pro-fibrotic 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. Overall design: We generated RNA-Seq data in MSCs differentiated in the presence of an adipogenic induction cocktail (0.5 mM isobutylmethylxanthine, 1 uM dexamethasone, 5 ug/mL insulin )treated with DMSO (0.1%), rosiglitazone (ROSI, 500 nM), or tributyltin (TBT, 50 nM) for 14 days. N=4 per treatment --> 12 RNA-Seq samples total.