[SAT-585] The Endocrine-Disrupting Chemical Tolylfluanid Disrupts Adipocyte Metabolism Via Glucocorticoid Receptor Activation
Brian A Neel, Robert M Sargis, Matthew J Brady. University of Chicago, Chicago, IL; University of Chicago, Chicago, IL.
Emerging data implicate environmental endocrine disrupting chemicals (EDCs) as contributors to the burgeoning global obesity and diabetes epidemics. These environmental toxins disrupt normal hormonal signaling in a manner that promotes excess adiposity and disturbs normal metabolism. The central role of adipose tissue in systemic energy metabolism and the bioaccumulation of lipophilic EDCs in the adipocyte lipid droplet make adipose tissue an important model to study the metabolic effects of EDCs. In an initial screen of putative metabolic disruptors, the fungicide tolylfluanid (TF) was found to robustly inhibit insulin signaling and glucose uptake in the 3T3-L1 adipocytes. Further analyses showed that TF inhibits insulin-stimulated Akt phosphorylation in primary murine and human adipocytes. In an interrogation of the insulin signaling pathway, TF inhibited PI3Kinase association with insulin receptor substrate-1 (IRS-1) through a downregulation of IRS-1 transcript and protein levels at concentrations from 10 nM to 1 μM after 24 hours in culture. This attenuation of insulin signaling led to an inhibition of leptin secretion as well as a broader shift in the adipokine secretory profile. The next aim was to determine the molecular mechanism of this alteration in insulin signaling. Previous work has shown that many EDCs bind to and activate various nuclear receptors. Because the glucocorticoid receptor (GR) is known to modulate adipocyte physiology, the effect of TF on GR activation was examined. Using the glucocorticoid-induced leucine zipper (GILZ) gene as a readout of GR activation, TF exhibited glucocorticoid-like activity, with IRS-1 expression correlating with the degree of GR activity. Interestingly, TF mimicked glucocorticoid action by acutely increasing and chronically decreasing insulin responsiveness through changes in IRS-1 levels. At equal levels of GR activity, TF increased insulin-stimulated lipogenesis to a similar extent as the active murine glucocorticoid corticosterone. Cellular fractionation assays also demonstrated that TF promotes the activating phosphorylation of GR, driving it from the cytoplasm into the nucleus. Collectively, these results demonstrate the ability of TF to inhibit insulin signaling through a specific downregulation of IRS-1, likely through GR activation. This novel molecular mechanism of EDC action supports a potential role for these chemicals in the pathogenesis of obesity and diabetes.
Sources of Research Support: The National Institutes of Health [T32-HL007237 supporting B.A.N.; K08-ES019176 and F32-ES017397 to R.M.S.] and by the Diabetes Research and Training Center [P60-DK020595].
Nothing to Disclose: BAN, RMS, MJB
Date: Saturday, June 23, 2012
Session Info: POSTER SESSION: Phytoestrogens & Endocrine Disrupting Chemicals (1:30 PM-3:30 PM)
Presentation Time: 1:30 pm
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