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

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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.