OR01-1 The acromegaly gene expression signature in human adipose tissue reveals possible new mechanisms for enhanced lipolysis and insulin resistance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR01-Cell Specific GH & IGF-1 Signaling
Basic
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:30 AM
Room 134 (Moscone Center)
Irit Hochberg*1, Dave Bridges2, Alan R Saltiel3, Ariel L Barkan3 and William F Chandler2
1Rambam Health Care Campus, Haifa, Israel, 2University of Michigan, Ann Arbor, MI, 3Univ of Michigan, Ann Arbor, MI
Context: Growth hormone has clinically important effects on adipose tissue, including stimulation of lipolysis and lipid oxidation; enhancing of lipoprotein lipase (LPL); inhibition of conversion of cortisone to cortisol and decrease in insulin sensitivity. Patients with acromegaly have impaired insulin sensitivity and increased lipolysis.
Aim: The objective of this study was to determine the effect of chronic excess growth hormone in acromegaly on gene expression in adipose tissue in humans.
Experimental design: We compared global gene expression in subcutaneous fat biopsies from 9 acromegaly patients undergoing transsphenoidal pituitary adenomectomy with that of 11 controls undergoing a similar surgery for non-functioning pituitary adenoma. The patients underwent pre-operative clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue from patients were assayed ex-vivo for lipolysis. mRNA was analysed by next-generation sequencing and bioinformatic analysis of transcript expression was performed.
Results: We observed enhanced ex vivo lipolysis in adipose tissue explants from acromegaly patients, which could be potentially explained by over a 6 fold induction in beta adrenergic receptor-3 expression and LPL expression that was 2 fold higher compared to controls. Interestingly, TSH-R expression was induced 6 fold, possibly contributing to induction of lipolysis. Expression of TCF7L2, a diabetes susceptibility gene whose expression in adipose tissue has been correlated with diabetes, was significatnly higher in acromegaly patients, and could be a factor in the growth hormone-induced insulin resistance. 11β-hydroxysteroid dehydrogenase type 1 expression was 4 fold lower in acromegaly patients. As expected, adipose tissue IGF-1 and IGF-BP3 expression was higher (3.7 fold and 2.4 fold respectively)  in acromegaly patients. Bioinformatic analysis identified over a hundred additional differentially expressed genes and transcripts in adipose tissue of acromegaly subjects compared to controls, including gene clusters for growth, lipid metabolism, energy homeostasis and apoptosis.
Conclusions: We have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of TCF7L2, beta adrenergic receptor-3, TSH-R and other significantly modified genes to the insulin resistance and enhanced lipolysis in acromegaly will enhance our understanding of the metabolic changes in fat tissue which are associated with acromegaly.

Nothing to Disclose: IH, DB, ARS, ALB, WFC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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