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发挥核心作用，包括 2糖尿病(DM)。与内脏脂肪组织一样，储存库特异性是脂肪组织生物学的中心特征 增值税(VAT)与代谢性疾病密切相关，而皮下脂肪组织(SAT)则相反 与新陈代谢健康有关。尽管这些疾病关联很重要，但这些机制 不同储存库的脂肪组织功能差异及其对全身代谢的影响仍然存在 定义不明确。我们的初步数据，基于单细胞/单核RNA测序和代谢 人脂肪组织表型，鉴定不同脂肪组织基质细胞(ASC)亚群 人类脂肪组织，包括炎症性内脏脂肪组织(VAT)特异性ASC亚群 特征，以及VAT和SAT中存在的成脂ASC亚群。我们还确定了一个重要的角色 细胞外基质(ECM)在调节脂肪组织代谢的仓库特异性差异中的作用。目标 这一建议的目的是定义人类ASC亚群对仓库特定差异的贡献 脂肪组织代谢及其在调节全身性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 增值税及其对全身新陈代谢的不利影响，而没有这种增值税特有的ASC 亚群负责SAT ASC对系统代谢的有益影响；VAT和 SAT ECM具有控制IM/FA-ASC平衡和功能的属性，从而调节特定于仓库的 脂肪组织对全身代谢控制的差异。我们将利用体内和体内实现我们的目标 体外细胞代谢表型，创新的2D和3D人类ASC-脂肪细胞-ECM培养系统，以及 小鼠人类异种移植模型，以询问ASC在调节系统代谢中的作用。正在完成 这项翻译科学建议将具有重要意义，因为它将解决关于以下方面的关键知识差距 不同储存库脂肪组织功能差异的机制及其与全身的关系 代谢性疾病，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的机制 全身代谢性疾病。

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.