Overweight and obesity are characterized by profound changes in adipose tissue mass. These changes reflect, in part, significant differences in the number and size of adipocytes that comprise adipose tissue. In the last four years, we have demonstrated that the transcription factor, cAMP Response Element Binding Protein (CREB) plays important roles in the development of new fat cells from preadipocytes via adipogenesis, and the survival of mature adipocytes by blocking apoptotic cell death. Additional preliminary data show that CREB regulates the expression of the pro-adipogenic signaling molecule, protein kinase B/Akt in 3T3-L1 preadipocytes and adipocytes. These data have lead us to hypothesize that CREB and specific Akt isoforms are necessary for adipogenesis, and stimulate this process by increasing the expression and/or activity of C/EBP alpha, beta, and PPARgamma2. To address this hypothesis we propose four Specific Aims. The first Specific Aim will determine whether CREB and each Akt are necessary for adipogenic conversion, and determine whether the time course for expression and/or activation of these factors is crucial in promoting adipocytes differentiation.
Specific Aim 2 will assess the impact of CREB and each Akt isoform on the expression and activity of the """"""""master adipogenic regulators"""""""", C/EBP alpha, C/EBP beta and PPARgamma2.
Aim 3 will evaluate the ability of CREB and each Akt isoform to induce adipogenesis in cells deficient in C/EBPs alpha, beta, or PPARgamma2, and whether these master regulators can drive adipocyte differentiation in cells lacking CREB or each Akt. Finally, Aim 4 will investigate whether activation of CREB initiates the same adipogenic program as conventional hormonal inducing agents, and identify genes regulated by CREB during adipogenic conversion using gene microarray technology. These studies comprise a comprehensive research program to determine the necessity of CREB and Akts 1, 2, and 3 for adipogenesis, and reveal underlying functional interactions between CREB, Akts, and the master adipogenic regulators, C/EBP alpha, beta, and PPARgamma2. Given the putative importance of CREB and Akt in adipogenesis, this research program is likely to have a significant impact on our understanding of obesity and related diseases.
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