White adipose tissue (WAT) development in vertebrates occurs through an increase in both the size and number of adipocytes residing in the tissue. The occurrence of several pathological conditions including NIDDM (Type II diabetes) is strongly correlated with both obesity and lipoatrophy. The adipocyte arises from a pluripotent mesenchymal stem cell that undergoes differentiation in response to endocrine and other external signals. While key transcriptional activators that regulate the final stages in the adipocyte differentiation pathway have been identified, the molecular mechanisms that initially cause an undifferentiated stem cell to adopt the adipocyte cell fate are not well elucidated. In addition, little is known about the cellular processes that maintain the functional phenotype of the mature adipocyte. Better understanding the molecular mechanisms that govern the growth and function of adipocytes may aid in the development of therapeutic agents used for the prevention and treatment of obesity and related diseases. Signals generate by the Notch receptors and their ligands may be one possible mechanism governing adipocyte differentiation and function as Notch signaling regulates both cell differentiation and homeostasis in mature tissues. The Notch receptors and ligands are expressed in adipogenic cells throughout differentiation and persists in the mature cell, yet little is known about how they regulate the adipocyte life cycle and function. The objective of this proposal is to specifically study the requirement for the Notch ligand Jagged 1 in adipogenesis and in the mature adipocyte through the use of gain- and loss-of-function models both in vitro and in vivo. To meet this objective, the following specific aims are proposed:
Specific Aim 1 : To delineate the functional role of Jagged1 during adipogenesis from a mesenchymal stem cell/ progenitor to a mature, specialized cell;
Specific Aim 2 : To determine the role of Jagged 1 in maintaining the phenotype of a mature functional adipocyte within adipose tissue.
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