Obesity develops when energy intake exceeds energy expenditure, leading to an accumulation of adipose tissue. The pandemic of excess adipose tissue is of increasing importance throughout the world. In addition to its own specific morbidities, obesity is linked to insulin resistance and the devastating metabolic syndrome of type 2 diabetes. The intricate balance of energy homeostasis is tightly regulated by a complex network of metabolic genes which respond to changing environmental conditions. Transcriptional regulation has recently been shown to extensively modulate adipocyte biology. We have discovered that a novel transcriptional coregulator, TRIP-Br2, is critical for maintaining energy homeostasis in mice. Our preliminary data from preadipocyte cell lines and TRIP-Br2 null mice leads us to propose an important role of TRIP-Br2 in adipocyte biology. Thus, the goal of this proposal is to determine the function and mechanism of TRIP-Br2 in energy metabolism in adipose tissue. I will test the hypothesis that disruption of TRIP-Br2 protects mice from diet- induced obesity through upregulation of energy expenditure with three specific aims.
For Specific Aim 1, I will physically and physiologically examine the TRIP-Br2 null mice to identify the in vivo mechanism for diet- induced obesity resistance observed in TRIP-Br2 KO mice. Completion of Aim 1, which will take place during K99 phase, will provide me with training in aspects of in vivo and ex vivo adipose physiology necessary to independently complete the R00 phase.
For Specific Aim 2, which will span the K99 and R00 phases, I will determine the molecular targets of TRIP-Br2 that contribute to the diet-induced obesity resistance phenotype in TRIP-Br2 null mice using genome-wide gene and protein expressions together with bioinformatics analysis. Completion of the subaim of Aim 2 proposed during the K99 phase will provide me with the training in analysis of complex datasets with computational biology necessary to independently to complete Aim 2 during the R00 phase.
For Specific Aim 3 (R00 phase), I will determine the composition of TRIP-Br2 transcriptional regulatory complex in adipocytes. Completion of this aim will allow me to link the TRIP-Br2 regulatory network with known gene regulatory system in adipocyte. These experiments are novel in that they combine mouse genetic, physiologic, and molecular biology approaches to examine the mechanistic role of TRIP-Br2 in energy metabolism. These studies will provide novel insights into the transcriptional regulation of adipocyte function and could potentially be used for developing therapeutic targets for obesity.
Obesity is a critical health problem in the US because it leads to fatal complications. These studies will determine the mechanisms contributing to high fat diet-induced obesity resistance in our mouse model. Understanding the gene targets will facilitate development of therapeutic strategies.
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