Abstract
Corticosteroids (CS) effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX) rats were given single doses of 50 mg/kg methylprednisolone (MPL) intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS-1), uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), fatty acid translocase (FAT) and glycerol-3-phosphate acyltransferase (GPAT) dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N)) and transcription factors. The oscillatory feature of endothelin-1 (ET-1) expression was depicted by a negative feedback loop. These integrated models provide testable quantitative hypotheses for these regulatory cascades.
Highlights
A major function of the hypothalmic/pituitary/adrenal axis (HPA-axis) involves regulating the production, storage, use, and distribution of substrates for systemic energy metabolism
The glucocorticoid receptor density (GR) mRNA concentration drops from the baseline level to the trough in 10 h and slowly returns to the baseline
Since receptor mRNA and receptor density data were absent for the infusion study, the resultant parameters from the acute study were used to simulate receptor dynamics in muscle during the infusion and receptor dynamics were fixed in the subsequent gene regulation modeling (Fig. 7)
Summary
A major function of the hypothalmic/pituitary/adrenal axis (HPA-axis) involves regulating the production, storage, use, and distribution of substrates for systemic energy metabolism. Glucocorticoid output from the adrenal cortex, which occurs with a circadian periodicity, serves to maintain adequate blood glucose in order to assure that sufficient glucose is available to fulfill the needs of vital organs, the brain. This is accomplished by adjusting both supply and demand. Glucocorticoids increase the synthesis and activity of enzymes in the gluconeogenic pathway in liver and kidney, as well as ancillary enzymes/pathways such as expression of aminotransferases and components of the urea cycle They control the release of gluconeogenic substrates from muscle and fat. They decrease glucose utilization in peripheral tissues which in part encompasses their anti-inflammatory and immunosuppressive actions
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