DESCRIPTION (provided by applicant): Fat distribution varies considerably, even among those with the same total body fat content. Increased central fat is associated with the metabolic syndrome. To define cell dynamic and molecular mechanisms that contribute, we established advanced methods to isolate, clone, and differentiate human abdominal subcutaneous, mesenteric, and omental preadipocytes. We found pronounced regional variation in the developmental factors, cAMP response element binding protein (CREB), CITED2, FOXO1, and certain homeobox (HOX) factors, that interact with each other to regulate lineage progression, replication, apoptosis, and differentiation in other cell types. Their expression profiles were consistent with regional variation in preadipocyte replication, differentiation, and apoptosis. We found two adipocyte precursor subtypes, one capable of more extensive replication, differentiation, and adipogenic transcription factor expression and less apoptosis in response to TNF alpha than the other. The former was most abundant in subcutaneous and least abundant in omental preadipocyte populations, potentially accounting for regional variation in capacities for replication, differentiation, and apoptosis. Our hypothesis is that adipocyte precursor subtypes, with distinct cell dynamic characteristics shaped by developmental regulators, contribute to regional differences in fat tissue function. Aim 1 is to test the hypothesis that developmental regulators underlie regional variation in preadipocyte function. Regulator activity will be manipulated using pharmacological and molecular approaches to test if cell dynamic features of preadipocytes from one depot can be made to resemble those of the others. Aim 2 is to test the hypothesis that developmental regulators contribute to the distinct cell dynamic characteristics of the two preadipocyte subtypes. We will determine expression patterns of developmental regulators in each subtype and manipulate expression of developmental factors to show if they regulate subtype cell dynamics or switching between subtypes. Aim 3 is to test the hypothesis that regional differences in preadipocyte subtype quantities or qualities cause differences in fat tissue function. These studies will elucidate cell dynamic and developmental mechanisms predisposing preadipocytes from different fat depots to acquire distinct characteristics responsible for regional obesity and the metabolic syndrome.
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