Cellular and molecular mechanisms of white adipose tissue regulation in development and disease

Yale University, New Haven CT

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Abstract

? DESCRIPTION (provided by applicant): The rates of obesity, which is defined as an excessive increase in white adipose tissue (WAT) mass, has increased rapidly over the last several decades and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity-linked disorders, such as diabetes, cardiovascular disease and certain types of cancer. Despite the importance of WAT in normal physiology and disease, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with differential risks of developing diabetes and other obesity-associated pathologies. However, the mechanisms that control WAT mass in distinct depots is not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipocyte precursors (APs). We have recently identified APs in vivo, allowing us to directly interrogate the mechanisms that control WAT mass and function in vivo. We have recently reported that there is an obesity-specific mechanism of adipogenesis. In addition, our preliminary data shows there are discreet periods of AP activation at separate life stages and that remarkable sex-specific differences in AP activation occur in obesity. We, therefore, hypothesize that distinct regulatory mechanisms control depot-specific WAT expansion in different physiologically relevant contexts. Furthermore, by identifying the initiating signals tha regulate the tissue-intrinsic control of WAT mass in specific depots we may be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. Here we will characterize depot-specific mechanisms of adipogenesis during key stages of embryonic and postnatal development, as well as the mechanisms driving sexually dimorphic WAT expansion and function in obesity. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and cardiovascular disease.