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2017 Cardiovascular Research Day Abstract Book

21 Exposure to PCB126

21 Exposure to PCB126 during the Nursing Period Significantly Impairs Early-Life Glucose Tolerance Keegan Sammons 1 • Sara Tenlep, MS 1 • Leryn Reynolds, PhD 1 • Hollie Swanson, PhD 1 • Kevin Pearson, PhD 1 1Pharmacology and Nutritional Sciences, University of Kentucky Undergraduate Polychlorinated Biphenyls (PCBs) are persistent environmental organic pollutants that are known to have detrimental health effects. In a mouse model in our lab, PCB126 exposure during pregnancy and nursing alters offspring body composition and glucose tolerance. The purpose of this study was to expose dams to PCB126 during the nursing period only. Female ICR mice were bred and half of the dams were exposed to either vehicle (safflower oil) or 1 µmole PCB126 per kg of body weight via oral gavage on postnatal days 3, 10, and 17 (n = 9/group). Offspring body weight, lean and fat mass, and glucose tolerance were measured. Both male and female offspring displayed normal body weights as well as body composition (p > 0.05). However, both male and female offspring that were exposed to PCBs during the nursing period had significantly impaired glucose tolerance at 3 weeks of age (p < 0.05). This persisted until 9 weeks of age in the female offspring (p < 0.05), but the difference disappeared as the male offspring aged (p > 0.05). Our earlier work suggests that in utero and postnatal PCB126 exposure predisposes offspring to having lower lean mass and impaired glucose tolerance later in life. However, our current study shows that exposure to PCB126 through the mother's milk impairs glucose tolerance in the short-term and is likely caused by impairments in insulin receptor signaling in the periphery as others have shown with direct PCB exposures in adult mice. Future experiments will investigate the mechanisms of dysfunction caused by in utero PCB126 exposure, which may be driving the increased risk of obesity and insulin resistance in adult offspring. 37

22 Regulation of Akt Signaling by NQO1 Joshua Preston 1 • Andrea Di Francesco, PhD 2 • Krystle Kalafut 2 • Tyler Rhinesmith 2 • Clara Di Germanio, PhD 2 • Michel Bernier, PhD 2 • Rafael de Cabo, PhD 2 1Pharmacology and Nutritional Sciences, University of Kentucky • 2 Translational Gerontology Branch, National Institute on Aging, National Institutes of Health Undergraduate Background: NQO1 is an inducible quinone reductase that participates in the cellular defense system in response to chemical and oxidative stress. By using NAD(P)H as electron donor, NQO1 enzymatic activity shifts the cellular redox state leading to a significant increase in the NAD+/NADH ratio. The propensity of NQO1 knockout mice to exhibit a diabetes-like phenotype and a null NQO1 polymorphism associated with metabolic syndrome phenotypes in humans suggests a role for this enzyme in cellular energetics and metabolism. Here, we explored a possible link between NQO1, an intracellular generator of NAD+, and nutrient-sensitive NAD+-dependent deacetylase activity in the regulation of Akt, which plays a central role in regulating cellular signaling and energy pathways critically involved in type 2 diabetes and associated metabolic disorders. Results: Pharmacological inhibition of NQO1 with the mechanism-based inhibitor Mac609 increased insulin-stimulated Akt phosphorylation in HepG2 and HeLa cell lines. Consistent with increased Akt activation, Mac609 promoted nuclear exclusion and inactivation of the downstream Akt targets, the gluconeogenic transcription factors forkhead box O1 (FOXO1) and O3 (FOXO3a) in liver-derived HepG2 cells treated with insulin. Conversely, siRNA-mediated NQO1 knockdown increased insulin- or serum-stimulated Akt phosphorylation. Similarly, MDA-MB-468 cells, which carry a polymorphic form of NQO1 that results in an absence of NQO1 protein and activity, showed markedly higher constitutive and insulin-stimulated Akt phosphorylation levels compared to an isogenic cell line stably expressing NQO1. We then explored the impact of pharmacological inhibition or genetic down-regulation of NQO1 on the global pattern of protein acetylation in HeLa cells. The reduction in NQO1 level and/or activity was associated with an increase in protein acetylation levels likely due to the inhibition of NAD+-dependent sirtuins. Lastly, cell treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) inhibited Akt phosphorylation in a dose- and time-dependent manner, thus recapitulating the effects of NQO1 on Akt activity. Conclusions: We have identified a molecular mechanism whereby NQO1 functions as a modulator of insulin/Akt signaling pathway. These findings have implications for future basic and translational research on pathways that control energy homeostasis and diabetes. 38

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