All ETDs from UAB

Advisory Committee Chair

W Timothy Garvey

Advisory Committee Members

Rita Cowell

Stuart J Frank

Yuchang Fu

Timothy R Nagy

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

For the past several decades, the prevalence of Type 2 Diabetes and the metabolic syndrome has been increasing. Insulin resistance is the central pathogenic event for these diseases. We previously reported that the NR4A family of orphan nuclear receptors augments insulin sensitivity in adipocytes. We now found that lentiviral mediated NR4A3 hyper-expression increased insulin stimulated glucose transport (ISGT) in C2C12 myocytes while NR4A3 knock-down exhibited opposite effect. We also examined the effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 trans-activation in C2C12 myocytes. PGA2 augmented ISGT and insulin stimulated AKT phosphorylation in C2C12 myocytes. Importantly, PGA2 treatment led to increased ISGT in NR4A3 over-expressing C2C12 myocytes while the sensitizing effect of PGA2 was diminished in NR4A3 knock-down myocytes. These novel results suggest that a working model that PGA2 augments insulin action in myocytes via a mechanism involving NR4A3, which provides a proof of principle for future anti-diabetic medication development. Exercise is used therapeutically to reverse insulin resistance. Interestingly, exercise was also reported to induce NR4A mRNA expression. Given the established role of NR4As in insulin sensitivity modulation, it was imperative to explore whether exercise regulates NR4A protein expression. Therefore, we measured muscle NR4A protein in 16 healthy young and 11 old males following acute (AE) and chronic (CE) resistance exercise. Muscle biopsies were performed at baseline and 24 hr after both AE and CE. NR4A1 levels are similar in young and old at baseline, increased by AE in young only, and reduced in young and old following chronic resistance training. NR4A3 protein levels are diminished in elderly subjects but are not affected by AE or CE. Our data indicate differential effects of age and exercise on muscle NR4A protein expression, which may shed a light to address whether NR4As are involved in the beneficiary effects of exercise.

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