Defining the role of an endothelial-adipocyte precursor axis in adipocyte hyperplasia

定义内皮脂肪细胞前体轴在脂肪细胞增生中的作用

• 批准号: 10586647
• 负责人: Matthew S Rodeheffer
• 金额: $ 56.28万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586647
• 关键词: Adipocytes; Adipose tissue; Adult; Aromatase; Biology; Cardiovascular Diseases; Cardiovascular system; Classification; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Estrogen decline; Estrogens; Estrone sulfotransferase; Fatty acid glycerol esters; Female; Glucocorticoid Receptor; Glucocorticoids; Gonadal Steroid Hormones; Hyperplasia; Imaging Techniques; Inflammatory; Knockout Mice; Link; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic dysfunction; Modeling; Molecular; Mus; Obesity; Obesity associated disease; Ovariectomy; Pathology; Pathway interactions; Pattern; Play; Population; Process; Production; Public Health; Receptor Signaling; Regulation; Role; Signal Transduction; Visceral; Visceral fat; Work; hypothalamic-pituitary-adrenal axis; lipid biosynthesis; male; multiplexed imaging; novel therapeutics; obesity development; obesogenic; response; sex; single-cell RNA sequencing; subcutaneous

Project Summary Obesity, which is defined as the excess accumulation of white adipose tissue (WAT) is associated with the development of numerous metabolic, inflammatory, and cardiovascular derangements. However, it is the accumulation of visceral adipose (VWAT) that is associated with metabolic diseases, while the accumulation of subcutaneous adipose (SWAT) is thought to protect against the development of obesity-associated disease. Sex hormones are known to influence both the accumulation of adipose, adipose distribution between VWAT and subcutaneous adipose (SWAT), and the development of metabolic disease, but the precise mechanisms by which sex hormones influence adipose function and distribution remain unclear. We have previously shown that there is an obesity-specific mechanism of adipogenesis that drives adipocyte hyperplasia in a sex-specific pattern. Estrogen plays a role in this process, where exogenous estrogen drives a female-like patterning (both VWAT and SWAT) of adipocyte hyperplasia in male mice, while the absence of systemic estrogen in female mice results in male-like patterning (VWAT only response). Our preliminary data indicates that in the absence of systemic estrogen, estrogen signaling still plays a direct role in VWAT adipocyte hyperplasia at the onset of obesity. We show here that it is VWAT endothelial cells that express aromatase and thereby produce the estrogen required for adipocyte hyperplasia in males and ovariectomized females. We propose that aromatase expression in VWAT endothelium is controlled by glucocorticoids, linking the VWAT-specific actions of estrogen to the hypothalamic-pituitary-adrenal (HPA) axis. Based on our preliminary data, we hypothesize that estrogen and glucocorticoids participate in an endothelial cell-adipocyte precursor axis that regulates obesogenic adipogenesis, thereby influencing distribution of WAT and impacting metabolic disease. Here we will establish the role of adipose- produced estrogen in obesity and metabolic disease, determine the mechanisms that regulate aromatase in VWAT endothelial cells and define the molecular mechanisms of that regulate estrogen action in adipocyte precursors.

项目摘要 肥胖被定义为白色脂肪组织(WAT)的过度堆积与 许多代谢、炎症和心血管紊乱的发展。然而，它是 内脏脂肪堆积(VWAT)与代谢性疾病相关，而内脏脂肪堆积 皮下脂肪(SWAT)被认为可以预防肥胖相关疾病的发展。性 已知激素既影响脂肪的积累，也影响VWAT和VWAT之间的脂肪分布 皮下脂肪(SWAT)和代谢性疾病的发展，但其确切的机制 性激素对脂肪功能和分布的影响尚不清楚。 我们之前已经证明，有一种肥胖症特有的脂肪生成机制驱动脂肪细胞 在特定性别的模式下的增生。雌激素在这一过程中发挥作用，其中外源性雌激素驱动 雄性小鼠脂肪细胞增殖的雌性样图案(VWAT和SWAT)，而缺乏系统性 雌性小鼠体内的雌激素导致类似雄性的图案(仅对VWAT有反应)。我们的初步数据显示， 缺乏全身雌激素，雌激素信号在VWAT脂肪细胞增殖中仍起直接作用 肥胖症发作。我们在这里表明，正是VWAT内皮细胞表达芳香化酶，从而产生 男性和去卵巢女性脂肪细胞增殖所需的雌激素。我们建议芳香酶 VWAT内皮细胞的表达受糖皮质激素的控制，将雌激素的VWAT特异性作用联系到 下丘脑-垂体-肾上腺(HPA)轴。根据我们的初步数据，我们假设雌激素和 糖皮质激素参与调节肥胖脂肪生成的内皮细胞-脂肪细胞前体轴， 从而影响WAT的分布并影响代谢性疾病。在这里，我们将确立脂肪的作用-- 肥胖和代谢性疾病中产生的雌激素，确定VWAT中芳香化酶的调节机制 并确定调控脂肪细胞前体雌激素作用的分子机制。