Sarah Traynor1,2, Shashwati Bhattacharya1,2, Kirill Batmanov1,2, Lan Cheng2,3, Angela Weller2,3, Natalie Moore1,2, Carmen Flesher1,2 and David Merrick1,2 1Department of Medicine, Division of Endocrinology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 2Institute for Diabetes Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 3Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA Corresponding author: david.merrickpennmedicine.upenn.edu Abstract

The distinct anatomic environment in which adipose tissues arise during organogenesis is a principle determinant of their adult expansion capacity. Metabolic disease results from a deficiency in hyperplastic adipose expansion within the dermal/subcutaneous depot; thus, understanding the embryonic origins of dermal adipose is imperative. Using single-cell transcriptomics throughout murine embryogenesis, we characterized cell populations, including Bcl11b+ cells, that regulate the development of dermal white adipose tissue (dWAT). We discovered that BCL11b expression modulates the Wnt signaling microenvironment to enable adipogenic differentiation in the dermal compartment. Subcutaneous and visceral adipose arises from a distinct population of Nefl+ cells during embryonic organogenesis, whereas Pi16+/Dpp4+ fibroadipogenic progenitors support obesity-stimulated hypertrophic expansion in the adult. Together, these results highlight the unique regulatory pathways used by anatomically distinct adipose depots, with important implications for human metabolic disease.

Received May 9, 2024. Accepted August 28, 2024.