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.

概括 积累的证据表明下半身（LB）脂肪分布，与内脏和总体无关 肥胖，会下降代谢疾病的风险，例如折磨约7-15％的美国人的2型糖尿病。 具有LB脂肪分布的绝经前女性，即与“苹果”形状相比 免受代谢疾病的保护。 LB（臀女性）和上半身（UB）皮下脂肪 组织（SAT）在代谢和内分泌功能上开发不同，并且有所不同。能力 脂肪沉积物通过增生（即招募脂肪祖细胞）扩展或改造，对 维持脂肪功能。体内研究表明，新的前膜细胞的外观速率 股骨（FSAT）中的脂肪细胞高于腹部SAT（ASAT）。此外，还有 脂肪细胞大小和代谢功能的仓库差异。 SATS内的微环境可能 来自不同沉积物的脂肪祖细胞自主差异导致的 在体内文化后的秘密和持久。我们将检验以下假设：LB的脂肪祖细胞 具有“苹果”形状和低FSAT质量的女性的脂肪沉积物具有更有限的重塑能力 1）无法招募脂肪祖细胞，2）减少增加脂肪储存的能力。我们进一步 假设UB和LB SAT的生长和代谢差异与 细胞组成及其分泌产品的差异，这些产品决定了微环境 每个仓库。朝着理解脂肪关联的基础机制的长期目标 分布和代谢健康，我们将使用单细胞RNASEQ询问细胞 ASAT和FSAT组成两组非肥胖，健康的绝经前妇女 - 一组 “梨形”和其他“苹果形状”，并从每个SAT中采样脂肪组织。我们将重点目的目标1 定义成纤维细胞/脂肪干细胞中细胞群体并测试其脂肪生成潜力。我们 将评估脂肪祖细胞的脂肪生成能力与体内脂肪分布的函数不同， 代谢状态以及捐赠者每个SAT中成熟脂肪细胞的大小和数量。 AIM 2将使用 LC MS/MS比较ASAT和FSAT的分泌组，以评估仓库的差异并将测试 不同表达的分泌因子对LB和UB AP的增殖和分化的影响 在具有损失和功能研究的文化中。我们希望这些分析将使我们发现 人类SAT沉积物重塑和保持健康功能的能力的标记物以降低风险 女性代谢疾病。这些工具对于未来对脂肪性别差异的研究将是无价的 组织功能，测试不同的SAT如何应对饮食挑战，并为 改善代谢状态并防止代谢疾病的发作。