What Were We Looking At?
Cushing’s Disease is caused by a pituitary tumor that constitutively secretes ACTH, resulting in chronically elevated cortisol levels. Excess glucocorticoids are known to be associated with increased adiposity, increased muscle breakdown and insulin resistance; however, the process by which these occur is not well understood. Therefore, we wanted to determine if there were genetic differences that may lead to these phenotypic results.
What Did We Do?
We were able to obtain human adipose tissue from patients undergoing surgery to have their tumors removed, those that secreted ACTH were in the Cushing’s group and those that were non-secreting were in the control group. We then did RNA sequencing on the adipose samples.
Additionally, we developed a mouse model of Cushing’s by treating c57BL6/J mice with dexamethasone in their drinking water and compared these with control mice receiving untreated water. Adipose and muscle tissue samples were excised and analyzed by qPCR analysis following 12 weeks of treatment.
What Did We Find?
Several metabolic pathways were upregulated (via multiple elevations in mRNA transcipts of genes involved in these specific pathways) in Cushing’s compared to controls including lipogenesis, gluconeogenesis, TCA cycle, glycogenesis and proteolysis. Data from the mouse tissue samples supported these human findings. A heatmap showing some of the several hundred differentially expressed genes is shown below
What Does it Mean?
These results suggest that there is a shift in various metabolic processes such as increased ability to breakdown glucose and protein products and utilize their respective metabolites for greater lipid storage.
These findings are consistent with the phenotype of Cushing’s disease. Increased fat synthesis and protein breakdown are associated with decreased muscle mass, increased fat mass and insulin resistance.
Where are We Going?
We are currently investigating potential genes involved in the direct actions of glucocorticoids on increased lipid accumulation and mechanisms by which glucocorticoid-induced muscle breakdown occurs.
–Innocence Harvey, MSc.
Doctoral Candidate in the Integrated Biomedical Science Program (Physiology Track).
Reference
I. Hochberg, I. Harvey, Q. T. Tran, E. J. Stephenson, A. L. Barkan, A. R. Saltiel, W. F. Chandler, D. Bridges, Gene expression changes in subcutaneous adipose tissue due to Cushing’s disease, J. Mol. Endocrinol. 55, 81–94 (2015). doi: 10.1530/JME-15-0119