Adiporedoxin and the Regulation of Adipocyte Function in Human Obesity

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 DESCRIPTION (provided by applicant): Adipocytes have dual roles as energy-storing and as endocrine cells, and both functions are critical to maintaining metabolic homeostasis. Adipocyte hormones (so-called adipokines) include leptin, adiponectin, and numerous other metabolically important proteins. Adiponectin is an especially important adipokine because it functions to enhance insulin action and prevent inflammation. In insulin resistant obese individuals, adiponectin production is low. Our studies in rodent adipocytes led to the discovery of a peroxiredoxin family member that we named adiporedoxin (Adrx). Adrx expression is highly enriched in both mouse and human adipocytes and Adrx protein is localized to the endoplasmic reticulum. Preliminary studies show that the expression of both Adrx mRNA and protein was directly correlated with levels of adiponectin within the tissue and inversely related to key markers of endoplasmic reticulum and cellular redox stress in human adipose tissue from young, lean and obese subjects. In addition, in diet- induced obese mice, Adrx expression was decreased and correlated with low levels of circulating high molecular weight (HMW) adiponectin, the most active form. The goal of this application is to determine the translational importance of Adrx in obese humans. Our central hypothesis is that Adrx acts as a redox sensor that links oxidative stress and inflammation in the adipocyte to the systemic redox state in order to regulate adipokine production and maintain systemic metabolic homeostasis. Our first specific aim is to determine if low expression of Adrx in adipose tissue of men and women with a range of obesity and glucose tolerance is associated with decreased assembly and secretion of adiponectin and with lower circulating levels of HMW and total adiponectin (and their ratio). The second aim is to determine if the expression of Adrx is affected by adipocyte and/or systemic insulin resistance and redox status. Aim 3 will use newly-differentiated human adipocytes to: a) test consequences of Adrx knockdown and overexpression on the secretome, insulin signaling, adipocyte metabolism, and redox status and b) the importance of Adrx for preventing adipocyte dysfunction in response to challenge of nutrient and oxidant stresses. The combination of proposed basic and clinical studies will fill important gaps in knowledge of the human adipocyte secretome and how it is dysregulated in obesity. In addition, this work will test the generalizability of our preliminary findings on Adrx and adiponectin expression in younger individuals, in an older population at high risk for metabolic disease. The proposed studies represent an important step toward future efforts to develop dietary and pharmacological approaches to improve the secretory and metabolic functions of human adipocytes, and will contribute to the development of useful biomarkers of adipocyte function in clinical and population studies.