Dissecting Adipose Depot-Selective Regulation of Gene Programs

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DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DK-102: Develop improved animal models of NIDDK diseases. Work from many laboratories over the last several years has highlighted different fat depots within the body being not only distinct by anatomical location, but also characterized by relatively unique gene expression programs. While a lot of overlap exists with respect to genes that dictate mature adipocyte function, is also clear that distinct fat pads express unique subsets of gene expression resulting in physiologically distinct adipose tissues. Our ultimate goal is to understand and manipulate gene expression in distinct fat pads as distinct clusters of genes that are manipulated at the level of entire clusters rather than at the level of the individual gene. Here, the laboratories of Stephen Farmer and Philipp Scherer have teamed up to pool their expertise and resources to address what we consider to be one of the most important questions in adipose tissue biology, the molecular basis for fat pad-specific gene expression. Our hypothesis is that these programs (and not individual genes) are being modulated in a fat pad specific way and are responsible for the unique characteristics of individual fat pads. The importance of brown adipose tissue in the adult human has garnered some renewed interest in the very recent past. Critical factors involved in the "browning of white adipocytes" have been identified, but remain to be further studied. One of these critical factors that modulate portions of a brown adipocyte program is PRDM16. Much remains to be learned about the modular nature of PRDM16-mediated gene expression. Therefore, we propose to address the issue of modular, fat pad-specific control of gene expression with the following here aims: SA1: What is the role of PPARg in different pads and how does it achieve fat pad specific gene expression? PPARg induces fat pad specific effects through differential association with a multitude of co-repressors and co-activators. Defining a mutation in helix 7 has enabled the Farmer group to manipulate PPARg activity in unique ways that can now be tested in vivo. SA2: What is the role of C/EBPa in the mature adipocyte? C/EBPa has been knocked out systemically. This causes a fairly complex phenotype that has profound implications on development. Using our novel techniques, we will be able to study for the first time the role of C/EBPa in mature adipose tissue selectively, independent of effects in the liver and on adipogenesis.SA3: What is the exact role of CtBP-1 and -2 in white adipocytes and how does this action differ in distinct white fat pads compared to their role in brown adipose tissue. CtBP-1 and -2 are co-repressors responsible for turning off the visceral white genes in response to PPARg ligands but they are also the repressors interacting with PRDM16 in brown adipose tissue. The selective, targeted activation of these transcriptional programs enabling a fat pad to expand without concomitant inflammation is key to improvements of the obesity-associated risks of metabolic dysfunction. PUBLIC HEALTH RELEVANCE: Understanding and manipulating gene expression in distinct fat pads as distinct clusters of genes remains a major challenge. We propose that the physiological properties of a given fat pad are the result of the discrete regulation of a relatively small number of modules that controlled at the level of entire clusters rather than at the level of the individual genes. In this proposal, a group of investigators with expertise in the in vitro analysis of transcriptional events (Steven Farmer, Boston University) has teamed up with a group with ample expertise in the generation of mouse models (Phil Scherer, UTSW, Dallas) in which these modules will be manipulated through targeted expression or elimination of these key transcription factors.