Hormonal Regulation of Fat Deposition

脂肪沉积的荷尔蒙调节

• 批准号: 8063036
• 负责人: JONATHAN M GRAFF
• 金额: $ 48.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063036
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Agonist; Biological; Biology; Cardiovascular Diseases; Cell Lineage; Cells; Clinical; Cues; Data; Deposition; Development; Diabetes Mellitus; Disease; Epidemic; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Replacements; Estrogens; Fatty Liver; Fatty acid glycerol esters; Food Supply; Gene Expression Profile; Genes; Genetic; Goals; Health; Healthcare; Hormonal; Hyperplasia; Hypertrophy; Injection of therapeutic agent; Intra-abdominal; Knock-out; LacZ Genes; Lead; Life; Maintenance; Malignant Neoplasms; Mediating; Menopause; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Obesity; Onset of illness; Operative Surgical Procedures; Ovariectomy; Ovary; Physiological; Play; Population Growth; Process; Property; RNA Interference; Reagent; Reporter; Research Design; Risk; Role; Signal Transduction; Stem cells; Stimulus; System; Testing; Therapeutic; Virus; Visceral; adipocyte biology; cardiovascular disorder risk; cell type; clinically relevant; design; engineering design; hormone regulation; in vivo; insight; new therapeutic target; protective effect; public health relevance; response; self-renewal; stem; stem cell niche; subcutaneous; tool

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.

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改变。现代生活提供了无与伦比的食物供应，导致肥胖在世界范围内流行，并造成糖尿病、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，在各种饮食、药物和激素刺激下扩大和缩小。例如，雌激素缺乏（如更年期）将脂肪重新分配到代谢失调的内脏脂肪库，从而诱发或触发糖尿病。相反，雌激素将沉积转移到具有代谢保护作用的皮下储库，从而减少代谢性疾病。我们的初步数据表明，重塑包括肥大和增生（干细胞募集）。在整个生命过程中形成的新脂肪细胞表明存在假定的脂肪生成干细胞。我们最近通过设计、工程和研究在脂肪谱系中表达分子报告基因的小鼠，发现了这样一种脂肪干细胞。这些独特的试剂，被称为Adipo-Trak，使我们能够可视化体内的脂肪干细胞，并跟踪它们的后代，因为它们分裂，迁移和发育成成熟的脂肪细胞；从而使我们能够评估雌激素依赖性重塑。肥胖增加造成的健康风险因脂肪组织沉积而异；腹腔内（内脏）脂肪组织（随着更年期增加）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。本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）和遗传学（脂肪谱系特异性雌激素受体敲除）操作，我们将利用我们新开发的Adipo-Trak小鼠对这些形态发生转化进行建模，并确定它们如何影响脂肪谱系规范。我们将明确雌激素重塑对脂肪干细胞、脂肪小生境细胞和脂肪细胞影响的机制基础。我们还将阐明生理和药理刺激如何调节脂肪组织的干细胞群和生长。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的新疗法特别相关的研究。