The roles of Gfd3 in adipogenesis and adipocyte function

描述（由申请人提供）：超重和肥胖是全球日益严重的问题。肥胖是美国的巨大健康负担，由于其相关病症的发病率，估计每年有>10%的卫生保健支出用于该问题。此外，这是儿科人群中令人担忧的问题。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，少数民族和经济弱势群体的比例甚至更高。虽然社会经济和文化因素显然起着重要作用，但肥胖的遗传学现在正在被剖析，现在有几个基因与这种疾病的易感性有关。了解这些基因对身体脂肪组成产生影响的机制可能会提供重要的线索，有助于制定新的战略，以帮助对抗肥胖及其并发症。生长分化因子3（Gdf 3）是TGF-β超家族的成员，在脂肪中表达。我们已经产生了具有该基因的纯合无效突变的小鼠。当维持高脂肪饮食时，这些基因敲除小鼠表现出对肥胖的抵抗力，表明在脂肪细胞分化和/或功能中可能起作用。该提案旨在进一步研究这种现象，可能导致药物干预，以帮助对抗这种疾病。该提议的具体目的是1）进一步确定白色脂肪组织内哪些细胞类型表达GDF 3 2）评估Gdf 3-/-小鼠代谢率增加的生理和分子贡献者3）进一步检查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.