Mechanisms regulating functional heterogeneity of subcutaneous adipose tissues in women

女性皮下脂肪组织功能异质性的调节机制

• 批准号: 10621904
• 负责人: Susan K Fried
• 金额: $ 64.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621904
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; American; Appearance; Apple; Biology; Body fat; Buttocks; Cell Fraction; Cells; Cellularity; Cessation of life; Clinical Research; Data; Deposition; Development; Dual-Energy X-Ray Absorptiometry; Endocrine; Event; Extracellular Matrix; Fatty acid glycerol esters; Femur; Fibroblasts; Future; Goals; Growth; Health; Heterogeneity; Human; Hyperplasia; Hypertrophy; Insulin Resistance; Intervention; Knowledge; Leg; Link; Lipodystrophy; Metabolic; Metabolic Diseases; Metabolism; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Paracrine Communication; Pear; Persons; Phenotype; Pilot Projects; Play; Population; Population Study; Premenopause; Process; Proliferating; Protein Analysis; Regulation; Risk; Role; Sampling; Sex Differences; Shapes; Signal Transduction; Stromal Cells; Testing; Thigh structure; Tissue Donors; Tissues; Visceral; Waist-Hip Ratio; Woman; adipose derived stem cell; autocrine; cell type; dietary; differential expression; experimental study; fasting glucose; gain of function; improved; in vivo; insight; lipid biosynthesis; loss of function; metabolic profile; paracrine; premature; prevent; progenitor; protective effect; recruit; sex; single-cell RNA sequencing; subcutaneous; tool; transcriptome

Summary Accumulating evidence indicates that lower body (LB) fat distribution, independent of visceral and total adiposity, decreases risk for metabolic diseases such as type 2 diabetes that afflict ~7-15% of Americans. Premenopausal women who have a LB fat distribution, i.e. `pear' as compared to `apple' shape, are protected from metabolic disease. LB (gluteal-femoral) and upper body (UB) subcutaneous adipose tissues (SAT) are developmentally distinct and vary in metabolic and endocrine function. The ability of adipose depots to expand or remodel via hyperplasia, i.e. recruitment of adipose progenitors, is critical for maintaining adipose function. In vivo studies indicate that the rates of appearance of new preadipocytes and adipocytes are higher in femoral (FSAT) than abdominal SAT (ASAT). In addition, there are also depot differences in adipocyte size and metabolic function. The microenvironment within SATs may result from cell autonomous differences in adipose progenitors from different depots that influence their secretome and persist after culture ex vivo. We will test the hypothesis that adipose progenitors from LB fat depots of women with `apple' shape and low FSAT mass have a more limited ability to remodel due to 1) an inability to recruit adipose progenitors, 2) decreased capacity to increase fat storage. We further hypothesize that depot differences in the growth and metabolism of UB and LB SATs are related to differences in cell composition and their secreted products that determine the microenvironment within each depot. Toward the long-term goal of understanding the mechanisms underlying the association of fat distribution and metabolic health in humans, we will use single cell RNAseq to interrogate the cell composition of ASAT and FSAT in two groups of non-obese, healthy premenopausal women – one with a `pear shape' and the other `apple shape' and sample adipose tissue from each SAT. We will focus Aim 1 on defining populations of cells in fibroblastic/adipose stem cells and test their adipogenic potential. We will assess how the adipogenic capacity of adipose progenitors differs as a function of body fat distribution, metabolic status, and the size and number of mature adipocytes in each SAT of the donor. Aim 2 will use LC MS/MS to compare the secretome of ASAT and FSAT to assess if depot differences and will test the effects of differentially expressed secreted factors on the proliferation and differentiation of LB and UB APs in culture with loss and gain of function studies. We expect that these analyses will allow us to discover markers for the ability of human SAT depots to remodel and maintain healthy function to decrease risk for metabolic disease in women. These tools will be invaluable for future studies of sex differences in adipose tissue function, testing how different SAT respond to dietary challenges, and developing interventions to improve metabolic status and prevent the onset of metabolic disease.

总结 越来越多的证据表明，下半身（LB）的脂肪分布，独立于内脏和总 肥胖症，降低代谢性疾病的风险，如2型糖尿病，困扰约7-15%的美国人。 具有LB脂肪分布的绝经前妇女，即与“苹果”形状相比的“梨”形状， 防止代谢疾病。LB（臀股）和上身（UB）皮下脂肪 组织（SAT）在发育上是不同的，并且在代谢和内分泌功能上变化。的能力 通过增生，即脂肪祖细胞的募集，使脂肪库扩张或重塑， 维持脂肪功能。体内研究表明，新的前脂肪细胞的出现率 脂肪细胞在股动脉（FSAT）高于腹动脉（ASAT）。此外还有 脂肪细胞大小和代谢功能的差异。SAT中的微环境可能 这是由于来自不同贮库的脂肪祖细胞的细胞自主差异， 分泌组，并在离体培养后持续存在。我们将检验来自LB的脂肪祖细胞 具有“苹果”形状和低FSAT质量的女性的脂肪库具有更有限的重塑能力， 1)不能募集脂肪祖细胞，2）增加脂肪储存的能力降低。我们进一步 假设UB和LB SAT在生长和代谢方面的贮库差异与以下因素有关： 细胞组成及其分泌产物的差异决定了细胞内的微环境 每个仓库为了实现长期的目标，了解脂肪组织的相关机制， 分布和代谢健康，我们将使用单细胞RNAseq来询问细胞 两组非肥胖、健康的绝经前妇女中ASAT和FSAT的组成-一组为 “梨形”和另一个“苹果形”，并从每个SAT中采集脂肪组织样本。我们将专注于目标1 定义成纤维细胞/脂肪干细胞中的细胞群，并测试其成脂潜力。我们 将评估脂肪祖细胞的成脂能力如何作为体脂分布的函数而不同， 代谢状态，以及供体每个SAT中成熟脂肪细胞的大小和数量。目标2将使用 LC MS/MS比较ASAT和FSAT的分泌组，以评估储药差异，并将检测 差异表达的分泌因子对LB和UB AP增殖和分化的影响 在培养中进行功能丧失和获得的研究。我们希望这些分析能让我们发现 人类SAT库重塑和维持健康功能以降低风险的能力的标志物 女性的代谢性疾病这些工具将是非常宝贵的未来研究性别差异的脂肪 组织功能，测试不同的SAT如何应对饮食挑战，并制定干预措施， 改善代谢状态，预防代谢性疾病的发生。