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 越来越多的证据表明，下半身 (LB) 脂肪分布与内脏脂肪和总脂肪无关。 肥胖可降低罹患代谢性疾病（例如 2 型糖尿病）的风险，约 7-15% 的美国人患有 2 型糖尿病。 具有 LB 脂肪分布（即“梨形”身材与“苹果”身材相比）的绝经前女性 防止 LB（臀股骨）和上半身（UB）皮下脂肪的侵害。 组织（SAT）在发育上是独特的，并且代谢和内分泌功能各不相同。 脂肪库通过增生扩大或重塑，即招募脂肪祖细胞，对于 维持脂肪功能的体内研究表明，新的前脂肪细胞的出现率。 股骨脂肪细胞（FSAT）高于腹部脂肪细胞（ASAT）。 SAT 内的微环境可能存在脂肪细胞大小和代谢功能的差异。 由于来自不同储存库的脂肪祖细胞的细胞自主差异影响了它们的 我们将检验来自 LB 的脂肪祖细胞的假设。 “苹果”身材和低 FSAT 质量的女性的脂肪库重塑能力更有限，因为 1) 无法募集脂肪祖细胞，2) 增加脂肪储存的能力下降。 认为 UB 和 LB SAT 的生长和代谢的储存差异与 细胞组成及其分泌产物的差异决定了细胞内的微环境 每个仓库的长期目标是了解脂肪关联的机制。 人类的分布和代谢健康，我们将使用单细胞 RNAseq 来询问细胞 两组非肥胖、健康绝经前女性的 ASAT 和 FSAT 组成——一组具有 “梨形”和其他“苹果形”以及每次 SAT 的脂肪组织样本 我们将重点关注目标 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。 将评估脂肪祖细胞的脂肪生成能力如何随着身体脂肪分布的变化而变化， 代谢状态，以及目标 2 将使用的每个 SAT 中成熟脂肪细胞的大小和数量。 LC MS/MS 比较 ASAT 和 FSAT 的分泌蛋白组，以评估储存差异并测试 差异表达分泌因子对LB和UB AP增殖和分化的影响 我们期望这些分析能让我们发现功能丧失和获得的文化。 人类 SAT 库重塑和维持健康功能以降低风险的能力标记 这些工具对于未来脂肪性别差异的研究非常有价值。 组织功能，测试不同 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。