Exposure of adipocytes to bisphenol-A in vitro interferes with insulin action without enhancing adipogenesis.
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ABSTRACT:
SUBMITTER: De Filippis E
PROVIDER: S-EPMC6104924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Insulin action initiates a series of phosphorylation events regulating cellular differentiation, growth and metabolism. We have previously discovered, in a mass spectrometry-based phosphoproteomic study, that insulin/IGF-1 signalling induces phosphorylation of retinoid x receptor alpha (RXRα) at S22 in mouse brown pre-adipocytes. Here, we show that insulin induces the phosphorylation of RXRα at S22 in both brown precursor and mature adipocytes through a pathway involving ERK, downstream of IRS-1 and -2. We also found that RXRα S22 phosphorylation is promoted by insulin and upon re-feeding in brown adipose tissue in vivo, and that insulin-stimulated S22 phosphorylation of RXRα is dampened by diet-induced obesity. We used Rxra knockout cells re-expressing wild type (WT) or S22A non-phosphorylatable forms of RXRα to further characterize the role of S22 in brown adipocytes. Knockout of Rxra in brown pre-adipocytes resulted in decreased lipid accumulation and adipogenic gene expression during differentiation, and re-expression of RxraWT alleviated these effects. However, we observed no significant difference in cells re-expressing the RxraS22A mutant as compared with the cells re-expressing RxraWT. Furthermore, comparison of gene expression during adipogenesis in the WT and S22A re-expressing cells by RNA sequencing revealed similar transcriptomic profiles. Thus, our data propose a dispensable role for RXRα S22 phosphorylation in adipogenesis and transcription in differentiating brown pre-adipocytes.
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Project description:Endocrine-disrupting chemicals interact with transcription factors essential for adipocyte differentiation. Exposure to endocrine-disrupting chemicals corresponds with elevated risks of obesity, but the effects of these compounds on human cells remain largely undefined. Widespread use of bisphenol AF (BPAF) as a bisphenol A (BPA) alternative in the plastics industry presents unknown health risks. To this end, we discovered that BPAF interferes with the metabolic function of mature human adipocytes. Although 4-day exposures to BPAF accelerated adipocyte differentiation, we observed no effect on mature fat cell marker genes. Additional gene and protein expression analysis showed that BPAF treatment during human adipocyte differentiation failed to suppress the proinflammatory transcription factor STAT1. Microscopy and respirometry experiments demonstrated that BPAF impaired mitochondrial function and structure. To test the hypothesis that BPAF fosters vulnerabilities to STAT1 activation, we treated mature adipocytes previously exposed to BPAF with interferon-? (IFN?). BPAF increased IFN? activation of STAT1 and exposed mitochondrial vulnerabilities that disrupt adipocyte lipid and carbohydrate metabolism. Collectively, our data establish that BPAF activates inflammatory signaling pathways that degrade metabolic activity in human adipocytes. These findings suggest how the BPA alternative BPAF contributes to metabolic changes that correspond with obesity.
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Project description:ObjectiveExposure to bisphenol A (BPA) has been shown to increase the prevalence of obesity and its related insulin resistance (IR). Ceramide is a sphingolipid known to facilitate the production of proinflammatory cytokines and subsequently exacerbate inflammation and IR during the progression of obesity. Here, we investigated the effects of BPA exposure on ceramide de novo synthesis and whether increased ceramides aggravate adipose tissue (AT) inflammation and obesity-related IR.MethodsA population-based case-control study was conducted to explore the relationship between BPA exposure and IR and the potential role of ceramide in AT in obesity. Next, we used mice reared on a normal chow diet (NCD) or a high-fat diet (HFD) to verify the results from the population study and then investigated the role of ceramides in low-level BPA exposure with HFD-induced IR and AT inflammation in mice treated with or without myriocin (an inhibitor of the rate-limiting enzyme in de novo ceramide synthesis).ResultsBPA levels are higher in obese individuals and are significantly associated with AT inflammation and IR. Specific subtypes of ceramides mediated the associations between BPA and obesity, obesity-related IR and AT inflammation in the obesity group. In animal experiments, BPA exposure facilitated ceramide accumulation in AT, activated PKCζ, promoted AT inflammation, increased the expression and secretion of proinflammatory cytokines via the JNK/NF-κB pathway, and lowered insulin sensitivity by disrupting IRS1-PI3K-AKT signaling in mice fed a HFD. Myriocin suppressed BPA-induced AT inflammation and IR.ConclusionThese findings indicate that BPA aggravates obesity-induced IR, which is partly via increased de novo synthesis of ceramides and subsequent promotion of AT inflammation. Ceramide synthesis could be a potential target for the prevention of environmental BPA exposure-related metabolic diseases.
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Project description:BackgroundExposure to common environmental substances, such as bisphenol A (BPA), has been associated with a number of negative health outcomes. In vivo, BPA is rapidly converted to its predominant metabolite, BPA-glucuronide (BPA-G), which has long been believed to be biologically inactive because it lacks estrogenic activity. However, the effects of BPA-G on cellular metabolism have not been characterized. In the present study we examined the effect of BPA-G on adipogenesis.MethodsThe effect of BPA-G on the differentiation of human and 3T3L1 murine preadipocytes was evaluated in vitro by quantifying lipid accumulation and the expression of adipogenic markers.ResultsTreatment of 3T3L1 preadipocytes with 10 μM BPA-G induced a significant increase in lipid accumulation, mRNA expression of the adipogenic markers sterol regulatory element binding factor 1 (SREBF1) and lipoprotein lipase (LPL), and protein levels of LPL, aP2, and adipsin. Treatment of primary human preadipocytes with BPA-G also induced adipogenesis as determined by aP2 levels. Co-treatment of cells with the estrogen receptor (ER) antagonist fulvestrant (ICI) significantly inhibited the BPA-G-induced increase in LPL and aP2 levels, whereas treatment with ICI alone had no effect. Moreover, BPA-G did not display any significant estrogenic activity.ConclusionsTo our knowledge, this study is the first to report that BPA-G induces adipocyte differentiation and is not simply an inactive metabolite. The fact that BPA-G induced adipogenesis and was inhibited by an ER antagonist yet showed no estrogenic activity suggests that it has no classical ER transcriptional activation function and acts through a pathway that remains to be determined.
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