Nrf as an oxidative stress and nutrient responsive transcription factor in calorie restriction
The purpose of the study performed in MANUSCRIPT I is to elucidate the role of Nrf2 in calorie restriction and identify a potential mechanism of Nrf2-dependent lipid regulation involved in weight loss and decreased fat storage. Few studies exist that have shown Nrf2 activation in adipose tissue (AT), and even fewer studies demonstrate the response of Nrf2 to nutrient status. The data presented in this study demonstrate that 1) The ARE, Nrf2, and classical downstream target expression is induced by calorie restriction in WAT, 2) Nrf2 induction bolsters the antioxidant capacity in vivo and in vitro, 3) Key regulators of calorie restriction and WAT lipid metabolism are induced by an Nrf2-dependent pathway, 4) Important enzymes involved in lipid uptake, lipogenesis, and lipolysis are Nrf2-dependent genes, and 5) CR mimetics and Nrf2 activators can decrease lipid content of adipocytes. ^ Nrf2 has a novel role in its response it metabolic stressors, nutrient overload, or nutrient deprivation, but the classical activation of Nrf2 by chemical-induced oxidative stress can be reconsidered in understanding how environmental contribute to development of fat mass or obesity. Many environmental toxicants are known to stimulate the ARE/Nrf2 signaling pathway, and it has been considered a hallmark of induction of oxidative stress. Most recently though, environmental chemicals are more persistent in the environment and more lipophilic, therefore being deposited in lipophilic tissues such as AT. The ability of these compounds to activate Nrf2 may not result in an antioxidant response, but can potentially alter the homeostasis of WAT and cause AT dysfunction. AT dysfunction is the hallmark of many diseases, and can be directly to related to obesity. In MANUSCRIPT II, 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) is studied for its ability to induce adipogenesis and lipid development in models of pre-adipocyte differentiation. ^ The ability of the compound to act as an obesogen in WAT, allows for Nrf2 to be studied in a mechanism of chemical-induced regulation of lipid metabolism. Therefore, the purpose of MANUSCRIPT II, was to demonstrate that environmental toxicants can alter Nrf2 expression and subsequent oxidative stress response to alter lipid metabolism in WAT. The observations in this study support 1) The role of BDE-99 in the development of excess lipids during adipocyte differentiation, and 2) A potential mechanism of decreased Nrf2-signaling during differentiation. ^ Lastly, MANSCURPT III, studies the ability of perinatal deltamethrin exposure to alter WAT metabolism. The focus of this study was to demonstrate that an environmental compound exposure during gestation and alter WAT metabolism and result in phenotypic changes. The observations in the study demonstrate 1) Nrf2 can be induced by chemical-exposure in WAT, 2) Perinatal-exposure to deltamethrin has a hermetic effect on gene expression that does not result in phenotypic changes as adults, 3) Deltamethrin could epigenetically reprogram gene expression, and potentially be involved in the development of susceptibility to obesity or metabolic diseases related to WAT metabolism. In summary, MANUSCRIPT III, represents a perinatal exposure model in which Nrf2 is downregulated in WAT and results in a subsequent down-regulation of genes involved adipogenesis, fat metabolism, and cytokine expression. In conclusion, this dissertation establishes a link between antioxidant response/oxidative stress and WAT metabolism through the ARE/Nrf2 signaling pathway and continues to demonstrate that Nrf2 activation is a hormetic effect and the timing, disease model, and length or intensity of activation need to be considered in order to maintain homeostasis of the vital signaling pathways regulated by Nrf2. (Abstract shortened by UMI.)^
"Nrf as an oxidative stress and nutrient responsive transcription factor in calorie restriction"
Dissertations and Master's Theses (Campus Access).