Hormonal Regulation of Fat Deposition

描述（由申请人提供）：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转导改变。现代生活提供了无与伦比的食物供应，导致肥胖症和继发性负面健康后果（如糖尿病，脂肪肝，心血管疾病，甚至癌症）在全球范围内流行。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，响应于各种饮食、药理学和激素刺激而膨胀和收缩。例如，雌激素缺乏（例如，绝经期）将脂肪重新分配到代谢适应不良的内脏脂肪库中，从而诱发或引发糖尿病。相反，雌激素将沉积转移到代谢保护性皮下仓库，从而减少代谢疾病。我们的初步数据表明，重塑涉及肥大和增生（干细胞募集）。新的脂肪细胞在整个生命过程中形成，表明存在假定的成脂干细胞。最近，我们通过设计、工程和研究在脂肪谱系中表达分子报告基因的小鼠，确定了这样一种脂肪干细胞。这些独特的试剂，称为Adipo-Trak，使我们能够在体内观察脂肪干细胞，并在它们分裂，迁移和发育成成熟脂肪细胞时跟踪它们的后代;从而使我们能够评估雌激素依赖性重塑。由于肥胖增加的健康风险取决于脂肪组织沉积;腹腔内（内脏）脂肪组织（随着绝经而增加）比皮下脂肪组织（由雌激素诱导）更容易患心血管疾病，糖尿病，癌症和其他疾病。这项建议的重点是描述雌激素如何以这种医学相关的方式重塑脂肪组织。通过整合手术（卵巢切除术），药理学（雌激素）和遗传（脂肪谱系特异性雌激素受体敲除）操作，我们将模拟这些形态发生的转变，并确定它们如何影响脂肪谱系规格使用我们新开发的Adipo-Trak小鼠。我们将明确雌激素对脂肪干细胞、脂肪龛细胞和脂肪细胞重塑作用的机制基础。我们还将阐明生理和药理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，从而突出那些与肥胖和糖尿病新疗法特别相关的研究。 公共卫生相关性：调节脂肪储存和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，例如受雌激素调节的基因。我们最近发现了脂肪干细胞，并发现它在脂肪组织质量的正常维持和对糖尿病治疗的反应中很重要。此外，脂肪谱系细胞对于由雌激素或雌激素缺乏诱导的医学相关脂肪重塑似乎至关重要。我们的目标是解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.