Hormonal Regulation of Fat Deposition

描述(申请人提供)：我们的总体目标是阐明控制脂肪组织形成和重塑的机制，并确定这些过程是否以及如何被雌激素信号改变。现代生活提供了无与伦比的食物供应，助长了肥胖的全球流行和糖尿病、脂肪肝、心血管疾病甚至癌症等继发性负面健康后果。因此，迫切需要更好地了解控制脂肪细胞形成和脂肪组织扩张的机制和分子。脂肪组织是高度动态的，对各种饮食、药物和激素刺激的反应是膨胀和收缩的。例如，雌激素缺乏(例如，更年期)会将脂肪重新分配到代谢不适应的内脏脂肪储存库，从而诱发或引发糖尿病。相比之下，雌激素将沉积转移到具有新陈代谢保护作用的皮下仓库，从而减少代谢性疾病。我们的初步数据表明，重塑包括肥大和增殖(干细胞募集)。这种新的脂肪细胞在整个生命过程中形成，这表明可能存在一种造脂干细胞。我们最近通过设计、设计和研究在脂肪谱系中表达分子记者的小鼠来鉴定这样一种脂肪干细胞。这些独特的试剂被称为ADIPO-TRAK，使我们能够在体内可视化脂肪干细胞，并在它们分裂、迁移和发育为成熟脂肪细胞的过程中跟踪它们的后代，从而使我们能够评估雌激素依赖的重塑。肥胖增加带来的健康风险取决于脂肪组织的沉积；腹内(内脏)脂肪组织(绝经后增加)比皮下脂肪组织(由雌激素引起)患心血管疾病、糖尿病、癌症和其他疾病的风险要大得多。这项提案的重点是描绘雌激素如何以这种与医学相关的方式重塑脂肪组织。通过集成手术(卵巢切除)、药物(雌激素)和遗传(脂肪谱系特异性雌激素受体敲除)操作，我们将使用我们新开发的ADIBO-TRAK小鼠对这些形态发生转换进行建模，并确定它们如何影响脂肪谱系规范。我们将确定雌激素重塑作用于脂肪干细胞、脂肪壁细胞和脂肪细胞的机制基础。我们还将阐明生理和药物刺激如何调节干细胞数量和脂肪组织的生长。这些研究旨在阐明脂肪生物学和代谢控制的新方面，以及雌激素如何提供保护作用，从而突出与肥胖症和糖尿病的新疗法特别相关的那些方面。 与公共健康相关：调节脂肪储存和新陈代谢的能力是基本过程。然而，肥胖和糖尿病的双重流行危及数百万人，并正在改变我们的医疗保健格局。这一危机可以通过识别控制脂肪组织形成、扩张和重塑的基因来解决--例如受雌激素调控的基因。我们最近鉴定了脂肪干细胞，并发现它在脂肪组织的正常维持和对糖尿病治疗的反应中非常重要。此外，脂肪系细胞似乎对雌激素或雌激素缺乏引起的医学上相关的脂肪重塑至关重要。我们的目标是揭开这些效应背后的发育、生理和分子机制，我们相信这将增强我们对脂肪细胞生物学的理解，并可能导致肥胖和糖尿病的新治疗靶点。

DESCRIPTION (provided by applicant): Our overall objective is to elucidate the mechanisms that control formation and remodeling of adipose tissues and to determine whether and how these processes are altered by estrogen signaling. Modern life has provided unparalleled access to food supplies, contributing to a worldwide epidemic of obesity and secondary negative health consequences such as diabetes, fatty liver, cardiovascular disease, and even cancer. Thus there is an urgent need to better understand the mechanisms and molecules that control formation of adipocytes and the expansion of adipose tissue. Adipose tissue is highly dynamic, expanding and shrinking in response to various dietary, pharmacologic and hormonal stimuli. For example, estrogen deficiency (e.g., menopause) redistributes fat into metabolically maladaptive visceral fat depots, thereby predisposing or triggering diabetes. In contrast, estrogen shifts deposition into metabolically protective subcutaneous depots, thereby reducing metabolic diseases. Our initial data indicate that remodeling involves both hypertrophy and hyperplasia (stem cell recruitment). That new adipocytes form throughout life indicates the presence of a putative adipogenic stem cell. We recently identified such an adipose stem cell by designing, engineering, and studying mice that express molecular reporters in the adipose lineage. These unique reagents, termed Adipo-Trak, enable us to visualize adipose stem cells in vivo, as well as to follow their descendents as they divide, migrate and develop into mature adipocytes; thereby allowing us to assess estrogen-dependent remodeling. Health risks due to increased adiposity vary depending on adipose tissue deposition; intra-abdominal (visceral) adipose tissue (increased with menopause) carries a much greater risk for cardiovascular disease, diabetes, cancers, and other disorders, than does subcutaneous adipose tissue (induced by estrogen). The focus of this proposal is to delineate how estrogen remodels adipose tissue in this medically relevant manner. By integrating surgical (ovariectomy), pharmacological (estrogen), and genetic (adipose lineage specific estrogen receptor knockouts) manipulations, we will model these morphogenic transformations and determine how they affect adipose lineage specification using our newly developed Adipo-Trak mice. We will define the mechanistic underpinnings of the estrogenic- remodeling effects on adipose stem cells, adipose niche cells and adipocytes. We will also elucidate how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue. These studies are designed to elucidate new aspects of adipose biology and metabolic control and how estrogen provides a protective effect, thereby highlighting those that are particularly relevant to new therapies for obesity and diabetes. PUBLIC HEALTH RELEVANCE: The ability to regulate fat storage and metabolism are fundamental processes. However, the dual epidemics of obesity and diabetes endanger millions and are altering our health care landscape. This crisis that could be addressed by identifying genes that control formation, expansion, and remodeling of adipose tissue-for example that regulated by estrogen. We recently identified the adipose stem cell and found that it is important in the normal maintenance of adipose tissue mass and the response to diabetes treatments. Further, adipose lineage cells appear critical for the medically relevant adipose remodeling induced by estrogen or estrogen-deficiency. Our goal is to unravel the developmental, physiological and molecular mechanisms underlying these effects, which we believe will enhance our understanding of adipocyte biology and may lead to novel therapeutic targets for obesity and diabetes.