Poster Session 1 - E3
1Neruja Loganathan, 1Emma McIlwraith, 1,2,3Denise Belsham
1 Dept. of Physiology, University of Toronto; 2 Dept. of Medicine, University of Toronto; 3 Dept. of Obstetrics and Gynaecology, University of Toronto, ON, Canada
Bisphenol A (BPA), an environmentally ubiquitous compound found in plastics, can linings and receipts, is termed an ‘obesogen’ as it leads to adipogenesis, lipogenesis and weight gain in animal models. AgRP and NPY are orexigenic neuropeptides produced in the hypothalamus and a dysregulation of these peptides can lead to hyperphagia and obesity. Using quantitative PCR, we have previously shown 100 micromolar BPA upregulated AgRP and altered NPY mRNA levels in six NPY/AgRP-expressing cell lines across 24 hours. We hypothesized that these BPA-mediated changes occur through induction of neuroinflammation and endoplasmic reticulum stress or through activation of nuclear receptors. We found that BPA increased mRNA levels of inflammatory cytokines (IL6, TNFalpha, IL10), ER stress markers (CHOP, GRP78, Bax/Bcl2) and nitric oxide synthases (iNOS, nNOS). These findings are currently being validated in hypothalamic primary culture. Western blot analysis showed BPA increased phosphorylation of the MAP kinases, JNK and ERK. Inhibition of JNK (SP600125) and MEK/ERK (PD0325901) partially abolished the BPA-mediated upregulation of AgRP, but not NPY, suggesting divergent mechanisms by which BPA regulates AgRP versus NPY. Furthermore, inhibition of NFkappaB activation (PS1145) and nuclear receptors, ERRgamma (GSK5182) and AhR (CH223191), did not have an effect on BPA-mediated AgRP and NPY induction. Future studies will focus on the nitric oxide pathway, using inhibitors to iNOS, nNOS and downstream effector, guanylyl cyclase. These studies will provide a potential mechanism by which BPA may act as an obesogen in the hypothalamus by increasing orexigenic neuropeptide expression, ultimately to increase food intake, often leading to obesity.