Mechanisms regulating functional heterogeneity of subcutaneous adipose tissues in women

摘要 越来越多的证据表明，下半身(Lb)脂肪分布独立于内脏和总 肥胖，降低患代谢性疾病的风险，如困扰约7%-15%的美国人的2型糖尿病。 具有LB型脂肪分布的绝经前女性，即‘梨’型与‘苹果’型相比，是 免受新陈代谢疾病的侵袭。LB(臀部-股骨)和上身(UB)皮下脂肪 组织(SAT)发育不同，代谢和内分泌功能各不相同。的能力 通过增殖来扩大或重塑脂肪库，即招募脂肪前体细胞，对于 维持脂肪功能。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)。此外，还有 储存脂肪细胞大小和代谢功能的差异。卫星内的微环境可能 由来自不同储存库的脂肪前体细胞自主差异所致，这些差异影响其 体外培养后分泌并持续存在。我们将检验这一假设，即来自LB的脂肪前体 “苹果”形和低FSAT质量的女性的脂肪库重塑能力更有限，原因是 1)无法招募脂肪前体细胞，2)增加脂肪储存的能力下降。我们进一步 假设UB和LBSAT在生长和新陈代谢方面的差异与 决定细胞内微环境的细胞组成及其分泌产物的差异 每个仓库。朝着了解脂肪关联的潜在机制的长期目标迈进 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、健康绝经前妇女的ASAT和FSAT的组成 ‘梨形’和另一个‘苹果形’，以及来自每个SAT的脂肪组织样本。我们将专注于目标1 关于确定成纤维细胞/脂肪干细胞中的细胞群体并测试其成脂潜力。我们 将评估脂肪前体细胞的成脂能力如何随着身体脂肪分布的不同而不同， 供者每个SAT中的代谢状态以及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，以评估是否库差异，并将测试 差异表达的分泌因子对LBAP和UBAP增殖分化的影响 在文化功能研究中有得失之分。我们希望这些分析将使我们能够发现 人类SAT仓库重塑和维持健康功能以降低风险的能力的标志 女性的代谢性疾病。这些工具对于未来研究脂肪的性别差异将是无价的。 组织功能，测试不同的SAT如何应对饮食挑战，并开发干预措施 改善代谢状态，预防代谢性疾病的发生。

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.