PDGFRα/PDGFRβ signaling balance modulates progenitor cell differentiation into white and beige adipocytes

Abstract

The relative abundance of thermogenic beige adipocytes and lipid-storing white adipocytes in adipose tissue underlie its metabolic activity. The roles of adipocyte progenitor cells, which express PDGFRα or PDGFRβ, in adipose tissue function have remained unclear. Here, by defining the developmental timing of PDGFRα and PDGFRβ expression in mouse subcutaneous and visceral adipose depots, we uncover depot specificity of pre-adipocyte delineation. We demonstrate that PDGFRα expression precedes PDGFRβ expression in all subcutaneous but in only a fraction of visceral adipose stromal cells. We show that high-fat diet feeding or thermoneutrality in early postnatal development can induce PDGFRβ lineage recruitment to generate white adipocytes. In contrast, the contribution of PDGFRβ lineage to beige adipocytes is minimal. We provide evidence that human adipose tissue also contains distinct progenitor populations differentiating into beige or white adipocytes, depending on PDGFRβ expression. Based on PDGFRα or PDGFRβ deletion and ectopic expression experiments, we conclude that the PDGFRα/PDGFRβ signaling balance determines progenitor commitment to beige (PDGFRα) or white (PDGFRβ) adipogenesis. Our study suggests that adipocyte lineage specification and metabolism can be modulated through PDGFR signaling.

Contribution of adipogenesis to healthy adipose tissue expansion in obesity

“…Following the depletion of endothelial (CD31 + ) and hematopoietic cells (CD45 + ) from the stromal vascular fraction of digested adipose tissue, PDGFRβ + cells can be subdivided into APCs and FIPs on the basis of LY6C and CD9 expression. individual adipose depots expand in mice in association with diet-induced obesity (60)(61)(62)(63)(64). Importantly, WAT expansion in mice with diet-induced obesity occurs in a depot-specific manner (46,60,(62)(63)(64).…”

“…individual adipose depots expand in mice in association with diet-induced obesity (60)(61)(62)(63)(64). Importantly, WAT expansion in mice with diet-induced obesity occurs in a depot-specific manner (46,60,(62)(63)(64). Epididymal WAT, representing an intraabdominal depot, expands in high-fat diet-fed (HFD-fed) adult male mice through both adipocyte hypertrophy and hyperplasia, while the inguinal (subcutaneous) depot in these same animals expands almost exclusively through cellular hypertrophy.…”

“…We and others have now demonstrated that visceral adipocytes emerging in association with HFD feeding originate, at least in part, from perivascular precursors expressing Pdgfrb (encoding the receptor PDGFRβ) (62,64). We have derived a doxycycline-inducible pulse-chase lineage tracing system (Pdgfrb rtTA ; TRE-Cre;Rosa26R mT/mG , or MuralChaser, mice) that allows fate mapping of Pdgfrb-expressing cells in response to various physiological stimuli (62).…”

Assembling the adipose organ: adipocyte lineage segregation and adipogenesis in vivo

“…Recently, it was shown that feeding PdgfRβ-Cre:mTmG male mice a Surwit diet (58% kcals from coconut/soybean oil and sucrose) results in high levels of mGFP + adipocytes in visceral (∼35%) and subcutaneous (∼70%) adipose depots after 4 weeks (Gao et al, 2018). This was interpreted as obesogenic adipogenesis from PdgfRβ + APs.…”

Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation

“…These include receptors such as PDGFRB (MIM: 173410) and TGFBR2 (MIM: 190182), the insulin growth factor IGF1 (MIM: 147440) and its binding partners IGFBP2 (MIM: 146731) and IGFBP3 (MIM: 146732), and the CXCR4 chemokine (MIM: 162643). [47][48][49][50][51][52][53] Furthermore, two of the enhancers harboring archaic variants at the highest frequencies interact with key adipocyte-differentiation regulators, such as KLF3 (MIM: 609392) and PRRX1 (MIM: 167420), 54,55 suggesting that introgression at AdMSC might have been adaptive in humans. In support of this notion, Dannemann and colleagues have found that more than half of aSNPs associated with gene expression in subcutaneous adipose tissue had increased in frequency over the last 10,000 years, whereas the majority of aSNPs had decreased in frequency over the same period of time.…”