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Title: Investigating the impact of c-Cbl deficiency in adipose tissue : its role in insulin sensitivity and adipokine production
Author: Ameen, G. I.
ISNI:       0000 0004 7659 0270
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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The worldwide obesity epidemic is now well recognised; obesity is a major problem not least because of the many serious metabolic complications that are associated with it. Cbl (Casitas B-lineage Lymphoma) is a receptor tyrosine kinase adaptor protein with E3 ubiquitin ligase activity that regulates receptor and nonreceptor tyrosine kinases, resulting in their down-regulation. c-Cbl is a key protein in the alternate pathway of insulin signalling to glucose transporter type 4 (GLUT4) translocation in 3T3-L1 adipocytes. However, the role of c-Cbl in adipokine expression is currently unknown. c-Cbl knockout (Cbl -/- ) mice were previously found to be more insulin sensitive and resistant to the deleterious effects of a high fat diet than control littermates, but the relevant mechanisms remain incompletely explored. In this study, the role of c-Cbl signalling was examined in white adipose tissue (WAT) of a Cbl -/- mouse model, specifically in glucose and lipid metabolism and adipokine production. c-Cbl knockout mice exhibited no changes in overall food intake or adiposity. However, there was increased ERK activation in WAT of Cbl -/- mice. The adipokine profile was altered in WAT of female Cbl -/- mice: leptin and RBP4 were increased, whereas adiponectin was reduced. These findings were confirmed in the 3T3L1 adipocyte cell line expressing shRNAs for c-Cbl. Furthermore, 17ß-estradiol increased RBP4 mRNA which was attributed to activation of oestrogen receptor alpha (ER-a). Regarding diet interventions, fasting decreased circulating concentrations of adiponectin in both male and female Cbl -/- mice, while leptin concentrations were decreased only in male Cbl -/- mice. However, RBP4 was increased in female Cbl -/- following a fast. On the other hand, Cbl -/- mice fed a HFD were protected from dietinduced insulin resistance. In addition, Cbl -/- mice fed a HFD exhibited an increase in energy expenditure (EE) together with decreased WAT leptin levels in males and lower circulating leptin in females. However, under a HFD c-Cbl depletion did not protect against increased RBP4 protein content in the liver. The findings of this thesis, taken together with the results from other studies, highlight the importance of c-Cbl depletion for the prevention and development of insulin resistance and T2D. This work is worthwhile not least because it holds promise for new treatments by increasing whole-body insulin sensitivity and energy expenditure. Further elucidation of the relevant molecular mechanisms will help develop a better understanding of the validity of c-Cbl inhibition as a therapeutic strategy for T2D.
Supervisor: Mora, Silvia ; Dockray, Graham Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral