Defining the lineage of thermogenic perivascular adipose tissue [PVAT v IWAT]. Defining the lineage of thermogenic perivascular adipose tissue [PVAT v IWAT]

Brown adipose tissue can expend large amounts of energy and thus increasing its amount or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. We applied single cell transcriptomic analyses, ex vivo adipogenesis assays, and genetic fate mapping to determine the identity of perivascular adipocyte progenitors. In mice, we found that thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra+; Ly6a+; Pparg-) and preadipocytes (Pdgfra+; Ly6a+; Pparg+). Progenitor and preadipocyte cells in PVAT shared transcriptional similarity with analogous cell types in inguinal white adipose tissue (IWAT), pointing towards a conserved hierarchical structure of adipose lineage cells. Interestingly, the aortic adventitia of adult animals contained a novel population of adipogenic smooth muscle cells (SMCs) (Myh11+; Pdgfra-; Pparg+) that contributed to perivascular adipocyte formation. Similarly, human PVAT contained presumptive fibroblastic and SMC-like adipocyte progenitors, as revealed by single nucleus RNAseq. Taken together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity Overall design: Transcriptome (mRNA) profiles of FACS isolated cell populations from the thoracic aorta perivascular fat (PVAT Progenitor cells and PVAT Preadipocytes) and inguinal white adipose tissue (IWAT) (DPP4+ Progenitors and ICAM1+ PreAdipocytes) from wild type 3 day old (P3) mixed male and female mouse pups were generated by deep sequencing, in triplicate, followed by DESeq2 analysis for differential expression of genes between the various groups.