Dissertation/Thesis Abstract

Elucidating the role of methionine sulfoxide reductase A (MsrA) in the development of insulin resistance
by Hunnicutt, JennaLynn Styskal, M.S., The University of Texas Health Science Center at San Antonio, 2015, 215; 10137700
Abstract (Summary)

The development of metabolic dysfunctions like diabetes and insulin resistance in mammals is regulated by a myriad of factors. Oxidative stress seems to play a central role in this process as recent evidence shows a general increase in oxidative damage and a decrease in oxidative defense associated with several metabolic diseases. These changes in oxidative stress can be directly correlated with increased fat accumulation, obesity and consumption of high calorie/high fat diets. Modulation of oxidant protection through either genetic mutation or treatment with antioxidants can significantly alter oxidative stress resistance and accumulation of oxidative damage in laboratory rodents. Antioxidant mutant mice have previously been utilized to examine the role of oxidative stress in other disease models, but have been relatively unexplored as models to study the regulation of glucose metabolism.

Our studies have focused on MsrA in mammalian systems and have utilized mice that lack MsrA (MsrA-/-) and that over express MsrA (MsrAmitoTg and MsrAcytoTg). Under normal conditions, our lab has shown that MsrA-/- mice are phenotypically similar to wildtype (WT) mice, but are susceptible to oxidative stress [244]. MsrAmitoTg and MsrAcytoTg are also phenotypically similar to WT (though oxidative stress resistance has not yet been tested). This indicates that excess methionine oxidation may not occur at basal ROS levels, which is supported by yeast studies [202]. In vivo, increasing adiposity has been associated with increases in oxidative stress, altered redox signaling and increased oxidative damage to cellular macromolecules in several disease models. It is also thought that adipose tissue-induced oxidative stress may be a primary factor in the etiology of obesity-induced metabolic diseases. When placed on a high fat (HF) diet to induce an increase in oxidative stress, MsrA-/- mice become more insulin resistant than WT mice whereas MsrAmitoTg mice are protected. The increase in insulin resistance in MsrA-/- mice is not due to further exacerbation of pathways thought to link oxidative stress and insulin resistance (JNK signaling or pro-inflammatory cytokine expression). These results suggest that oxidative damage to proteins may play an important role in obesity-induced insulin resistance.

Indexing (document details)
Advisor: Musi, Nicholas
Commitee: Ikeno, Yuji, Levine, Rodney, Liu, Feng, Tardif, Suzette
School: The University of Texas Health Science Center at San Antonio
Department: Cellular and Structural Biology
School Location: United States -- Texas
Source: MAI 55/05M(E), Masters Abstracts International
Subjects: Cellular biology, Biochemistry, Physiology
Keywords: Diabetes, Insulin resistance, Methionine, Methionine sulfoxide reductase A, Oxidative stress
Publication Number: 10137700
ISBN: 978-1-339-93379-5
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