Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis

Abstract

Objective The capacity to generate new adipocytes from precursor cells is critical for maintaining metabolic health. Adipocyte precursor cells (APCs) constitute a heterogenous collection of cell types; however, the contribution of these various cell types to adipose tissue expansion in vivo remains unknown. The aim of the current study is to investigate the contribution of Dpp4+ progenitors to de novo adipogenesis. Methods Single cell analysis has identified several transcriptionally distinct subpopulations of APCs, including Dpp4+ progenitor cells concentrated in the connective tissue surrounding many organs, including white adipose tissue (WAT). Here, we generated a Dpp4 CreER mouse model for in vivo lineage tracing of these cells and their downstream progeny in the setting of basal or high fat diet (HFD)-stimulated adipogenesis. Results Dpp4 CreER mice enabled specific temporal labeling of Dpp4+ progenitor cells within their native connective tissue niche. Following a dietary chase period consisting of chow or HFD feeding for 18 weeks, Dpp4+ progenitors differentiated into mature adipocytes within the gonadal and subcutaneous WAT. HFD stimulated adipogenic contribution from Dpp4+ cells in the gonadal but not the subcutaneous depot. Flow cytometry analysis revealed that Dpp4+ progenitors give rise to DPP4(−)/ICAM1+ preadipocytes in vivo . HFD feeding did not perturb the flux of Dpp4+ cell conversion into ICAM1+ preadipocytes in gonadal WAT. Conversely, in subcutaneous WAT, HFD feeding/obesity led to an accumulation of ICAM1+ preadipocytes without a corresponding increase in mature adipocyte differentiation. Examination of non-classical murine visceral depots with relevance to humans, including omentum and retroperitoneal WAT, revealed robust contribution of Dpp4 + progenitors to de novo adipogenesis, which was further stimulated by HFD. Conclusion Our data demonstrate that Dpp4+ interstitial progenitor cells contribute to basal adipogenesis in all fat depots and are recruited to support de novo adipogenic expansion of visceral WAT in the setting of HFD-induced obesity.

Single-nuclei Transcriptome of Human AT Reveals Metabolically Distinct Depot-Specific Adipose Progenitor Subpopulations

“…In mice, DPP4 + interstitial progenitor cells can form adipocytes in all depots but are induced to make adipocytes only in gonadal AT with obesity. 17 We used immunofluorescence (IF) microscopy with the IM-ASC specific marker TM4SF1 (transmembrane 4 L six family member 1), a surface tetraspanin to identify the location of IM-ASC. TM4SF1 + CD31 -IM-ASC were identified in the perivascular niche, distinct from TM4SF1 + CD31 + EC (Figure 3G).…”

“…We now know that this approach lacks rigor, as scRNAseq data from mice and humans demonstrate substantial heterogeneity in ASC and adipocytes. 5,6,16,17 Our goal was to apply snRNAseq analysis to banked frozen AT and describe the complete transcriptome of human VAT and SAT. We studied VAT and SAT samples from a cohort of lean human subjects and subjects with obesity.…”

“…CD9 hi ASC described by Marcelin et al were associated with VAT fibrosis and insulin resistance and overlap with our IM-ASC subpopulation. In mice, DPP4 + interstitial progenitor cells can form adipocytes in all depots but are induced to make adipocytes only in gonadal AT with obesity 17.…”

ExAdEx: A simple method to maintain human adipose tissue in long-term cultures reveals differential expansion of adipose progenitor cell subpopulations in fibrotic and pro-inflammatory micro-environments.

“…However, knowing the potential of APCs to undergo differentiation into myo broblasts when exposed to an in ammatory or brotic environment, it is tempting to speculate that the CD54 subpopulation will display a pro-brogenic/pro-in ammatory phenotype in the pathological model. Accumulation of CD54 + APCs in subcutaneous adipose tissue of high-fat-diet-induced obese mice without a corresponding increase in mature adipocyte differentiation support this hypothesis 15 . The role of CD142 APCs in adipogenesis is more controversial because this subpopulation is described as fully adipogenic or as inhibitor of adipogenic differentiation via paracrine effects 16 .…”

Immune Cell Regulation of White Adipose Progenitor Cell Fate

“…However, PDGFRα + CD9 low cells almost completely disappeared with AT fibrosis upon HFD feeding ( 33 ). Recently, a highly proliferative dipeptidyl peptidase-4 (DPP4) + APC population was identified that gives rise to highly adipogenic ICAM1 + preadipocytes as well as a CD142 + adipogenic cell population, which was further studied by DPP4-Cre mediated lineage tracing experiments ( Figure 1 ) ( 26 , 34 ). Moreover, various other cell surface molecules have been described to distinguish APC and preadipocyte populations and we recently showed that the amino acid transporter ASC-1 regulates the commitment of APCs to become either white or beige adipocytes ( 35 , 36 ).…”