The increase in adiposity in obese individuals results from an increase in the number of adjpocytes as well as the size of individual fat cells. Consequently, understanding the mechanisms regulating preadipocyte proliferation and differentiation will provide valuable information that will aid in the search for safe and effective therapeutics to reduce the growing incidence of obesity in the modern world. Additionally, obese individuals are more likely than their lean counterparts to develop insulin resistance, which leads to type 2 diabetes. In this regard, it is important to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. During the last several years, we and others have embarked on a detailed and systematic endeavor to define the transcriptional events and associated signaling pathways regulating preadipocyte growth and differentiation. We have also been committed to defining the mechanisms, which regulate insulin sensitivity in the adipocyte as well as those that control production of adipocytokines involved in overall energy balance. Our studies have contributed to the demonstration that C/EBPbeta plays an important role during adipogenesis by initiating a very early event leading to expression of the two master regulators of adipogenesis, PPARgamma and C/EBPalpha. This process also involves activation of the MEK/ERK signaling pathway by insulin and effectors of cAMP signaling. In fact, we have recently demonstrated that phosphorylation of C/EBPbeta at a consensus ERK/GSK3 phosphoacceptor site (Thr188) is required for the induction of C/EBPalpha and adiponectin expression during adipogenesis. The goal of the proposed studies is to continue with this endeavor to understand the molecular mechanisms regulating adipogenic gene expression by performing the investigations outlined in the following specific aims: 1. Identify the phosphoacceptor sites in C/EBPbeta regulating preadipocyte proliferation and differentiation. 2. Identify regulatory factors associating with C/EBPbeta in response to phosphorylation of select kinase sites. 3. Define the function of C/EBPbeta-associated proteins in regulating adipogenic gene expression. It is anticipated that these studies will contribute significantly to our understanding of the molecular mechanisms controlling adipocyte formation and function and ultimately lead to strategies to combat obesity and its associated disorders.
