This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The development of obesity is multifactorial and includes interactions between variant alleles and environments that predispose individuals toward development of the disease. Other components of obesity, based on variations in epigenetic programming, have been established by the strong evidence obtained from human epidemiological and animal studies that link nutritional status during in utero and early post-natal growth to the development of obesity and diabetes in adults. To investigate epigenetic contributions to obesity, we have developed an animal model based upon phenotypic variation of obesity in genetically identical mice. Using global gene expression analyses, we have identified a set of coordinately regulated developmental genes in adipose tissue that are associated with the development of a robust obesity phenotype in mice after feeding a high fat diet. These genes include an antagonist of Wnt signaling, secreted frizzled related protein 5 (Sfrp5) and the imprinted gene mesoderm specific transcript (Mest). Additionally, variations of Sfrp5 and Mest expression in adipose tissue biopsies performed on young mice prior to exposure to dietary fat can predict animals that were most susceptible to the development of dietary fat-induced obesity at a later age. In this proposal, we will use a retroviral-delivered inducible transgenic approach to examine the mechanism associated with the coordinated regulation of Sfrp5 and Mest and to determine how these genes modulate lipogenesis and adipocyte differentiation. We will also identify genomic targets associated with variable expression of Sfrp5 and Mest in adipose tissue to determine whether epigenetic differences are present within these elements. Future experiments will evaluate these mechanisms and associated genes as potential therapeutic targets for the treatment of obesity.
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