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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肥胖被定义为白色脂肪组织（WAT）的过度积累，与许多代谢、炎症和心血管紊乱的发展。然而，它是与代谢疾病相关的内脏脂肪（VWAT）的积累，而皮下脂肪（SWAT）被认为可以预防肥胖相关疾病的发展。性别众所周知，激素会影响脂肪的积累以及 VWAT 和脂肪之间的分布。皮下脂肪（SWAT）和代谢疾病的发展，但其确切机制性激素对脂肪功能和分布的影响仍不清楚。我们之前已经证明，存在一种肥胖特异性的脂肪生成机制，可以驱动脂肪细胞以性别特异性模式增生。雌激素在此过程中发挥作用，其中外源性雌激素驱动雄性小鼠脂肪细胞增生的雌性样模式（VWAT 和 SWAT），而缺乏全身性雌性小鼠中的雌激素会导致类似雄性的模式（仅 VWAT 反应）。我们的初步数据表明，在在缺乏全身雌激素的情况下，雌激素信号传导仍然在 VWAT 脂肪细胞增生中发挥直接作用肥胖的发作。我们在此表明，正是 VWAT 内皮细胞表达芳香酶，从而产生男性和卵巢切除的女性脂肪细胞增生所需的雌激素。我们建议芳香酶 VWAT 内皮细胞的表达受糖皮质激素控制，将雌激素的 VWAT 特异性作用与下丘脑-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 的分布并影响代谢疾病。在这里，我们将确定脂肪的作用—— 在肥胖和代谢疾病中产生雌激素，确定调节 VWAT 中芳香酶的机制内皮细胞并定义了调节脂肪细胞前体中雌激素作用的分子机制。