Distinct locations of different white adipose depots suggest anatomy-specific developmental regulation, a relatively understudied concept. Here, we report a population of Tcf21lineage cells (Tcf21LCs) present exclusively in visceral adipose tissue (VAT) that dynamically contributes to VAT development and expansion. During development, the Tcf21lineage gives rise to adipocytes. In adult mice, Tcf21LCs transform into a fibrotic or quiescent state. Multiomics analyses show consistent gene expression and chromatin accessibility changes in Tcf21LC, based on which we constructed a gene-regulatory network governing Tcf21LC activities. Furthermore, single-cell RNA sequencing (scRNA-seq) identifies the heterogeneity of Tcf21LCs. Loss of Tcf21promotes the adipogenesis and developmental progress of Tcf21LCs, leading to improved metabolic health in the context of diet-induced obesity. Mechanistic studies show that the inhibitory effect of Tcf21on adipogenesis is at least partially mediated via Dlk1expression accentuation.