The role of mitochondrially derived oxidative stress in the development of insulin resistance in the adipocyte
2015-09
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The role of mitochondrially derived oxidative stress in the development of insulin resistance in the adipocyte
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2015-09
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The number of people worldwide living with type-2-diabetes (T2D) is increasing at an alarming rate. In 2014, approximately 9% of the adult population worldwide was suffering from diabetes, with greater than 90% suffering from the type-2 form of the disease. One prominent risk factor for the development of T2D and insulin resistance is obesity. Ninety percent of type-2-diabetics are overweight or obese, highlighting the striking link between the two diseased states. Although T2D has been studied for years, the underlying mechanisms outlining the development of obesity induced insulin resistance remain poorly understood. Currently, it is well established that adipose tissue inflammation plays a major role in the induction of insulin resistance. Preliminary experiments using inflammatory cytokines to induce insulin resistance in adipocytes suggested that mitochondria maybe a site of oxidant accumulation resulting from transcriptional down-regulation of key mitochondrial antioxidants. Because oxidative stress is a hallmark feature of obese, insulin resistant adipose tissue, I was interested in identifying important metabolic pathways that were regulated by oxidative stress, independent of inflammation, within the adipocyte itself. Knockdown of Peroxiredoxin-3 (Prdx3) in adipocytes provided a tool that not only mimicked what was seen in diseased states, but also allowed for mechanistic study of the direct effects of mitochondrially generated oxidative stress on adipocyte insulin sensitivity. Importantly, these data revealed that silencing Prdx3 in adipocytes resulted in increased oxidative stress and insulin resistance mediated by rictor oxidation, decreased mTORC2 activity and subsequent decreases in S473-AKT phosphorylation.
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University of Minnesota Ph.D. dissertation.September 2015. Major: Integrative Biology and Physiology. Advisor: David Bernlohr. 1 computer file (PDF); v, 155 pages.
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