Date of Award
Master of Science
Naima Moustaid Moussa
Michael B. Zemel, Jay Whelan, John Koontz
Recent studies showed that adipocytes secrete angiotensin II (All) and express AII receptors, suggesting a role of adipose tissue in obesity-associated hypertension. However, the physiological actions of All in adipocytes remain unclear. This thesis study was designed to investigate the role of angiotensin II, a hypertensive hormone, in adipose tissue metabolism. We hypothesized that All may exert these effects by directly stimulating lipogenesis. To address this issue, we used murine 3T3-L1 as a cell model and the fatty acid synthase (FAS) gene as a lipogenic marker. We demonstrated that All up-regulates the FAS gene at the transcriptional level. In order to identify All regulatory sequences in the FAS promoter, we transfected fusion constructs linking various deletions of the FAS promoter to the luciferase reporter gene into 3T3-L1 adipocytes. We mapped the All responsive sequences to the previously identified insulin responsive sequences (-62 to -46) in the proximal region of the FAS promoter. Furthermore, we demonstrated that a mutation in the insulin response element abolishes not only insulin but also All responsiveness of the FAS gene. Since Adipocyte Determination and Differentiation factor 1, ADD1, has been postulated as a transcription factor in the regulation of adipocyte genes, we investigated the role of ADD1 in All regulation of the FAS gene. We demonstrated that overexpression of a dominant negative form of ADD1 in 3T3-L1 adipocytes markedly attenuates FAS induction by All. In conclusion, our data indicate that All exerts insulin like effects on the FAS gene by targeting similar regulatory sequences and transcription factors as insulin and suggest that paracrine effects of All in adipocytes contribute to adipocyte hypertrophy.
Standridge, Melissa Kay, "Angiotensin II regulation of adipocyte metabolism. " Master's Thesis, University of Tennessee, 2000.