Pdgfrβ+ Mural Preadipocytes Contribute to Adipocyte Hyperplasia Induced by High-Fat-Diet Feeding and Prolonged Cold Exposure in Adult Mice

Abstract

Summary The expansion of white adipose tissue (WAT) in obesity involves de novo differentiation of new adipocytes; however, the cellular origin of these cells remains unclear. Here, we utilize Zfp423GFP reporter mice to characterize adipose mural (Pdgfrβ+) cells with varying levels of the preadipocyte commitment factor Zfp423. We find that adipose tissue contains distinct mural populations, with levels of Zfp423 distinguishing adipogenic from inflammatory-like mural cells. Using our “MuralChaser” lineage tracking system, we uncover adipose perivascular cells as developmental precursors of adipocytes formed in obesity, with adipogenesis and precursor abundance regulated in a depot-dependent manner. Interestingly, Pdgfrβ+ cells do not significantly contribute to the initial cold-induced recruitment of beige adipocytes in WAT; it is only after prolonged cold exposure that these cells differentiate into beige adipocytes. These results provide genetic evidence for a mural cell origin of white adipocytes in obesity, and suggest that beige adipogenesis may originate from multiple sources.

Sorting out adipocyte precursors and their role in physiology and disease

“…The hypothesis of a perivascular origin of adipogenesis is also supported by mural cell expression of Zfp423 (Gupta et al 2012;Vishvanath et al 2016). Zfp423 is a multizinc finger transcription factor that regulates preadipocyte Pparγ expression and adipocyte differentiation in vitro and in vivo (Gupta et al 2010).…”

Heterogeneity of adipose tissue in development and metabolic function

“…At the cellular level, adipogenesis occurs in two major phases: first, precursors are committed to preadipocytes, and second, preadipocytes terminally differentiate into mature lipid-laden adipocytes (Rosen and MacDougald, 2006;Rosen and Spiegelman, 2014). Although the latter process has been studied in detail, the origin and identity of the adult white adipocyte progenitor niche remain a subject of debate (Vishvanath et al, 2016).…”

“…Interestingly, PdgfRβ expression only partially overlapped with GFP expression, indicating that preadipocytes derive from a subset of specialized PdgfRβ + pericytes (Gupta et al, 2012). Recent studies suggest that differentiation from Zfp423 + precursors occurs predominantly in pgWAT, a depot where adipocyte hyperplasia substantially contributes to increased tissue mass (Jeffery et al, 2015;Vishvanath et al, 2016;Wang et al, 2013). As indicated above, these data are in line with mesenchymal stem cells giving rise to adipocytes given that similar to mesenchymal stem cells, fluorescence-activated cell scanning (FACS)-sorted pericytes are multipotent, even after long-term passaging in culture (Crisan et al, 2008).…”

Adipose tissue in control of metabolism

“…Alternatively, Sca1 + progenitor cells (a subpopulation of adipogenic progenitors) can be induced and differentiated into brown-like adipocytes with bone morphogenetic protein 7 (BMP7) stimulation in the skeletal muscle and subcutaneous white fat (Schulz et al 2011). On the other hand, studies have shown that beige adipocytes can be derived from interconversion from white adipocytes or through transdifferentiation of matured white adipocytes in WAT (Himms-Hagen et al 2000, Barbatelli et al 2010, Rosenwald et al 2013, given that PDGFRα + preadipocytes are not recruited and do not significantly contribute to cold-induced WAT browning (Lee et al 2015b, Vishvanath et al 2016. In addition, Lee and coworkers show that the newly observed UCP1 positive cells derived from adiponectin + unilocular white adipocytes rather than PDGFRα + preadipocytes in inguinal WAT (Lee et al 2015b).…”