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Title: An allostatic view to lipid metabolism and energy homeostasis : the role of SREBP1 and Insig-1
Author: Hagen, R. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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I examined whether lipid allostatic compensatory allostatic mechanisms were present that could maintain adipose tissue development under stress conditions. For this I used the global SREBP1c KO mouse model as tool. As a key lipogenic gene it could be expected that genetic ablation of SREBP1c may result in a reduced white adipose tissue (WAT) phenotype in vivo. However the SREBP1c knockout mouse model had normal body and fat pad mass when fed a chow diet. I propose that maintenance of normal WAT development was possible through allostatic responses which involved decreased Insig-1 and upregulation of SREBP1a and 2. I addressed whether this SREBP1/Insig-1 allostatic loop was also observed in humans. I observed a downregulation of Insig-1 and maintained maturation of SREBP1 levels in WAT from morbidly obese insulin resistant human subjects. These SREBP1/Insig perturbations were recapitulated using an insulin resistant in vitro adipocyte cell model (3T3-L1) that allowed more in depth characterisation of the allostatic loop. Reduction of Insig-1mRNA in 3T3-L1 cells line to a similar level as observed in humans resulted in increased lipogenic and adipogenic capacity. I addressed whether selective disruption of a specific lipid pathway exerts a feedback mechanism response on the SREBP1 pathway and specific SREBP1 regulated pathways using the 3T3-L1 adipocyte cell line as an in vitro model. Perturbation of desaturase and phosphatidylcholine biosynthesis resulted in increased SREBP mRNA expression associated with a decrease in Insig mRNA expression during 3T3-L1 adipogenesis. These results support the concept of allostatic mechanisms designed to maintain the homeostasis of lipid metabolism as potential pathogenic mechanisms contributing to the development of obesity even in the presence of insulin resistance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available