ABSTRACT The parenchymal cell of adipose tissue is the white adipocyte, which is now understood to be a dynamic and active participant in metabolic homeostasis. Adipocytes store and release energy as needed, they coordinate physiological functions throughout the body via the elaboration of “adipokines”, and they have associations with human disease traits. Understanding the diversity of human adipocytes has been challenging, because of the technical difficulties inherent in working with large, fragile cells. We have now used advanced single nuclear sequencing techniques to circumvent this issue, and have now identified seven distinct subpopulations of human white adipocytes. There are many questions remaining, including whether there are more subpopulations in different adipose depots, what their functions are, and how they develop. In this proposal we will address these issues using a combination of phenotyping modalities, combined with experimental manipulations of signaling molecules and transcription factors that are predicted to affect adipocyte subpopulation development and function. Furthermore, we will associate these subpopulations with human metabolic disease traits. Finally, a key deliverable of this proposal is a Human Adipose Tissue Knowledge Portal, which will assimilate the data generated here and integrate it with data from other groups, facilitating standardization of experimental protocols, data analysis, and nomenclature. The resulting database will be a community resource and the starting point for a new era of adipose tissue biology.

NARRATIVE Adipocytes are central regulators of metabolic function and dysfunction. We have recently identified several subpopulations of human white adipocytes using single nucleus RNA-seq, although we still know little about how they develop, what their functions are, and where they reside in the fat pad. The studies in this proposal will address these issues using state-of-the-art multi-omic technologies, and will allow us to model specific subpopulations in vitro, enabling further downstream studies. Finally, we will build and populate a Human Adipose Tissue Knowledge Portal to disseminate our findings and those of other groups to the community at large.