ACTH-treated rats: a model to study IGFR-PI3K regulon

An increase in prevalence of metabolism-associated disorders worldwide poses an enormous financial burden on our current medical systems globally. This cluster of disorders includes obesity, insulin resistance, hypertension and coronary artery disease, collectively known as the metabolic syndrome disorders. The underlying pathogenesis is often attributed to interactions between genetic and environmental factors. Reliable biomarkers for early detection of these complex disorders have remained elusive. Genome-wide expression profiling is presented here in an attempt to identify high level interactions between genes and regulatory pathways. An unique 10K rat spotted oligonucleotide-array was used to identify transcriptome profiles of ACTH-treated compared with saline-treated Sprague-Dawley rats. This ACTH rodent model has been shown to exhibit traits and phenotypic manifestations of these disorders similar to those observed in humans. Heart and kidney profiles were analysed due to their high susceptibility to changes in homeostasis leading to metabolism-associated disorders. Quantitative RT-PCR was used to validate the microarray data. We have identified specific differential gene expression signatures as a result of ACTH administration. Gene annotation analyses have mapped those genes to a variety of cellular functions including signal transduction, carbohydrate/lipid metabolism, and cell organization and biogenesis. Interestingly, the majority of novel genes identified was mapped onto pathways involved in the signaling networks of insulin resistance and exerts an effect on regulation of intermediary metabolism and cell organization. The significance of this work is two fold; firstly, use of transcriptome based profiling at genomic level is feasible in identifying genetic signatures in these disorders, as is observed in oncology research and secondly, identification of novel candidate genes and networks associated with these disorders elucidate regulatory pathways that have potential to be developed further in clinical settings. Keywords: disease state comparison Gene expression of ACTH-treated Sprague-Dawley rats (n=10) was compared to saline-treated SD rats (n=9, 1 died of complications). 4 replicates for heart and 6 replicates for kidney. For heart, randomly pooled (rat #1,3,5,7 etc) ACTH-treated samples (n=5) were hybridised to pooled saline-treated samples (n=9); and vice versa for kidney. This was to investigate biological differences in gene expression for an ACTH effect on the overall rat genome. Control arrays to look for within group differences were conducted prior to this (data not shown).