ipocytes have higher expression of short stature homeobox 2 (Shox2) and glypican-4 (GPC4), which repress lipolysis and insulin sensitivity, respectively (24-27), whereas visceral adipose tissue has higher levels of HoxC8 and HoxA5, which regulate browning and adipogenesis (28, 29). In addition to subcutaneous and visceral fat, WAT in other depots may have distinct functions and effects on metabolism. White adipocytes within dermal layers are developmentally distinct from subcutaneous WAT (30) and play roles in wound healing, hair development, and pathogen resistance (31). Bone marrow adipose tissue (MAT) is also a distinct depot and includes two distinct subtypes (32): constitutive MAT (cMAT), concentrated in the distal skeletal bones, and regulated MAT (rMAT), which is diffusely distributed in the spine and proximal limb bones and is regulated in response to environmental factors (33, 34). MAT plays important roles in bone metabolism and osteoblastic activity (35). Interestingly, MAT is not depleted in calorically deficient states and may be a major source of circulating adiponectin (36, 37). Intra-depot heterogeneity in adipose tissue. A growing body of evidence indicates that adipocytes, even within a single fat pad, are heterogeneous in nature both genetically and metabolically (Figure 1B and refs. 38-41). This was initially suggested by a bimodal size distribution of adipocytes in mice with fat-specific ablation of the insulin receptor or hormone-sensitive lipase (HSL) (42, 43). Recent studies using clonal cell analysis and single-cell RNA-Seq further highlight this heterogeneity. Thus, white preadipocytes with low levels of CD9 are more adipogenic, whereas preadipocytes with high CD9 are more profibrotic and proinflammatory (44). By combining clonal analysis and lineage tracing, Lee et al. identified at least three functionally and developmentally distinct subpopulations of white preadipocytes in mice characterized by unique gene expression profiles and high expression of the marker genes Wilms tumor-1 (Wt1), transgelin, and myxovirus-1 (Mx1), termed types 1-3, respectively (45). Likewise, single-cell transcriptomic profiling of human preadipocytes and mesenchymal progenitor cells (46) has identified up to four adipocyte subtypes, including a beige/brite thermogenic subtype and a subtype specialized for leptin secretion.
