Depot-specific regulation of metabolism by adipose tissue stromal cell subpopulations

脂肪组织在肥胖相关代谢性疾病的发病机制中起着核心作用， 2型糖尿病（DM）。贮库特异性是脂肪组织生物学的中心特征，如内脏脂肪组织 (VAT)与代谢疾病密切相关，而相比之下，皮下脂肪组织（SAT） 与代谢健康有关。尽管这些疾病的重要性，机制， 在脂肪组织功能及其对全身代谢的影响方面， 定义不好。我们的初步数据，基于单细胞/单核RNA测序和代谢 人脂肪组织的表型，鉴定不同的脂肪组织基质细胞（ASC）亚群， 人脂肪组织，包括内脏脂肪组织（VAT）特异性ASC亚群，其具有炎性 特征，以及VAT和SAT中存在的脂肪形成ASC亚群。我们还确定了一个重要的作用， 细胞外基质（ECM）在调节脂肪组织代谢中的特定贮库差异中的作用。的目标 这项建议的目的是确定人类ASC亚群对特定仓库差异的贡献， 脂肪组织代谢，以及它们在调节全身胰岛素抵抗中的作用。我们将测试中央 炎症性VAT特异性ASC亚群介导不良代谢表型的假说 VAT及其对全身代谢的有害影响，而缺乏这种VAT特异性ASC 亚群负责SAT ASC对全身代谢的有益作用;并且VAT和 SAT ECM具有控制IM/FA-ASC平衡和功能的特性，从而调节特定仓库 脂肪组织控制全身代谢的差异。我们将使用体内和体内 体外细胞代谢表型分析，创新的2D和3D人类ASC-脂肪细胞-ECM培养系统，以及 小鼠人异种移植模型，以询问ASC在调节全身代谢中的作用。完成 这一转化科学提案将是重要的，因为它将解决一个关键的知识差距， 脂肪组织功能差异的基础机制及其与全身性疾病的关系 代谢疾病，定义人类ASC异质性并表征新的ASC亚群 与胰岛素抵抗相关，并阐明这些细胞群调节胰岛素抵抗的机制。 全身性代谢疾病。

Adipose tissue plays a central role in the pathogenesis of obesity-associated metabolic disease including type 2 diabetes (DM). Depot-specificity is a central feature of adipose tissue biology, as visceral adipose tissue (VAT) is strongly linked to metabolic disease, while in contrast, subcutaneous adipose tissue (SAT) is associated with metabolic health. Despite the importance of these disease associations, the mechanisms that underlie depot-specific differences in adipose tissue function and their effect on systemic metabolism remain poorly defined. Our preliminary data, based on single cell/single nuclear RNA sequencing and metabolic phenotyping of human adipose tissue, identify distinct adipose tissue stromal cell (ASC) subpopulations in human adipose tissue, including a visceral adipose tissue (VAT)-specific ASC subpopulation with inflammatory features, and an adipogenic ASC subpopulation present in VAT and SAT. We also identify an important role for the extracellular matrix (ECM) in regulating depot-specific differences in adipose tissue metabolism. The goals of this proposal are to define the contribution of human ASC subpopulations to depot-specific differences in adipose tissue metabolism, and their role in regulating systemic insulin resistance. We will test the central hypothesis that an inflammatory VAT-specific ASC subpopulation mediates the adverse metabolic phenotype of VAT and its detrimental effects on systemic metabolism, while absence of this VAT-specific ASC subpopulation is responsible for the beneficial effects of SAT ASC on systemic metabolism; and that VAT and SAT ECM have properties that control IM/FA-ASC balance and function, thus regulating depot-specific differences in adipose tissue control of systemic metabolism. We will accomplish our goals using in vivo and in vitro cellular metabolic phenotyping, innovative 2D and 3D human ASC-adipocyte-ECM culture systems, and mouse human xenograft models to interrogate the role of ASC in regulating systemic metabolism. Completing this translational science proposal will be significant because it will address a critical knowledge gap regarding mechanisms that underlie depot-specific differences in adipose tissue function and its relation to systemic metabolic disease, define ASC heterogeneity in humans and characterize novel ASC subpopulations associated with insulin resistance, and elucidate the mechanisms by which these cell populations regulate systemic metabolic disease.