| Obesity is an ever-growing problem of our society and, therefore, understanding the underlying endocrine causes is vital to both the prevention and treatment of this disease. This present thesis work was undertaken to better understand the impact of Acylation Stimulating Protein (ASP), an adipokine, on the physiology and pathophysiology of the adipose tissue. I have demonstrated, for the first time, that ASP participates in the recruitment of preadipocytes to become adipocytes (differentiation process). Although, the ASP effects were comparable to those of insulin, preliminary microarray analysis indicates that the early intracellular signaling pathways are likely quite different for both hormones. Furthermore, I have identified and begun to characterize an ASP receptor initially identified as C5L2. I have demonstrated that binding affinity of ASP and C3a (immediate ASP precursor) to C5L2 is similar to that observed in cells that are responsive to ASP (triglyceride synthesis stimulation, TGS). I have also shown, for the first time, that C5L2 is expressed in human adipose tissue, human skin fibroblasts and 3T3-L1 preadipocytes. Finally, the ASP signaling pathway resulting in increased TG synthesis has began to be explored using a "shot gun" approach. This initial phase of research has provided evidence of the involvement of phospholipase C and phosphoinositide 3-kinase in ASP signaling. Overall, the data presented in this thesis defines more clearly ASP-cell interaction and reveals potential targets for pharmacological agents that may prevent or slow down development of obesity in the future. |
