The roles of Gdf3 in adipogenesis and adipocyte function

描述(申请人提供)：超重和肥胖是世界范围内日益严重的问题。肥胖症是美国巨大的健康负担，据估计，由于相关疾病的发病率，每年用于这一问题的医疗支出有10%。此外，这在儿科人群中是一个令人担忧的问题。最近的一项估计表明，15.5%的美国儿童目前超重或肥胖，在过去20年中翻了一番，少数族裔和经济困难群体的比例更高。虽然社会经济和文化因素显然发挥了重要作用，但肥胖症的遗传学现在正在被剖析，几个基因现在与这种疾病的易感性有关。了解这些基因对身体脂肪成分发挥作用的机制，可能会提供重要的线索，有助于开发新的战略，帮助对抗肥胖及其伴发疾病。生长分化因子3(GDF3)是转化生长因子-β超家族的成员，表达于脂肪中。我们已经产生了该基因纯合子零突变的小鼠。当维持高脂肪饮食时，这些基因敲除的小鼠表现出对肥胖的抵抗力，这表明可能在脂肪细胞分化和/或功能中发挥作用。这项建议旨在进一步研究这一现象，可能导致药物干预，以帮助抗击这种疾病。这项建议的具体目的是：1)进一步确定白色脂肪组织中哪些细胞类型表达GDF3；2)评估GDF3-/-小鼠代谢率增加的生理和分子因素；3)进一步研究GDFS在成熟脂肪细胞中的作用。

DESCRIPTION (provided by applicant): Overweight and obesity are growing problems worldwide. Obesity is a tremendous health burden for the U.S. with estimates of >10% of health care expenditures devoted annually to the problem, due to morbidity from its associated conditions. Moreover, this is an alarming issue in the Pediatrics population. A recent estimate indicates that 15.5% of American children currently overweight or obese, doubling in the past 2 decades, with even higher rates among minority and economically disadvantaged groups. While socioeconomic and cultural factors clearly play an important role, the genetics of obesity is now being dissected and several genes are now implicated in the susceptibility to this disorder. Understanding mechanisms by which these genes exert their effects on body fat composition may provide important clues that will aid in developing new strategies to aid in the war on obesity and its co-morbid conditions. Growth differentiation factor 3 (Gdf3) is a member of the TGF-b superfamily, expressed in adipose. We have generated mice with a homozygous null mutation of this gene. When maintained on a high fat diet, these knockout mice exhibit resistance to obesity, suggesting a possible role in adipocyte differentiation and/or function. This proposal aims to study this phenomenon further, potentially leading to pharmacologic interventions to help combat this disease. The specific aims of this proposal are 1) to further define which cell types within white adipose tissue express GDF3 2) to assess the physiologic and molecular contributors to the increased metabolic rates of Gdf3-/- mice 3) to further examine GDFS's roles in the mature adipocyte.