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Multilayer-omics Reveal Sex- and Depot-Dependent Adipose Progenitor Cell Heterogeneity

ABSTRACT: White adipose tissue (WAT) harbors functionally diverse subpopulations of adipose progenitor cells that differentially impact tissue plasticity in a sex- and depot-dependent manner. To date, the molecular basis of this cellular heterogeneity has not been fully defined. Here, we describe a multilayered omics approach to dissect adipose progenitor cell heterogeneity in three dimensions: progenitor subpopulation, sex, and anatomical localization. We applied state-of-the-art mass spectrometry methods to quantify 4870 proteins in eight different stromal cell populations from perigonadal and inguinal WAT of male and female mice and acquired transcript expression levels of 15477 genes using RNA-seq. Notably, our data highlight the molecular signatures defining sex differences in PDGFRb+ preadipocyte differentiation and identify regulatory pathways that functionally distinguish adipose tissue PDGFRb+ subpopulations. Together, the multilayered omics analysis provides unprecedented insights into adipose stromal cell heterogeneity.

ORGANISM(S): Mus musculus

PROVIDER: GSE165600 | GEO | 2022/01/26

REPOSITORIES: GEO

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Multilayered Omics Revealsl Sex- and Depot-Dependent Adipose Progenitor Cell Heterogeneity

Project description:White adipose tissue (WAT) harbors functionally diverse subpopulations of adipose progenitor cells that differentially impact tissue plasticity in a sex- and depot-dependent manner. To date, the molecular basis of this cellular heterogeneity has not been fully defined. Here, we describe a multilayered omics approach to dissect adipose progenitor cell heterogeneity from in three dimensions: progenitor subpopulation, sex, and anatomical localization. We applied state-of-the-art mass spectrometry methods to quantify 4870 proteins in eight different stromal cell populations from perigonadal and inguinal WAT of male and female mice and acquired transcript expression levels of 15477 genes using RNA-seq. Notably, our data highlight the molecular signatures defining sex differences in PDGFR+ preadipocyte differentiation and identify regulatory pathways that functionally distinguish adipose tissue PDGFRb+ subpopulations. The data are freely accessible as a resource at "Pread Profiler. Together, the multilayered omics analysis provides unprecedented insights into adipose stromal cell heterogeneity.

2023-03-11 | PXD023829 | Pride

Multilayer-omics Reveal Sex- and Depot-Dependent Adipose Progenitor Cell Heterogeneity

Project description:Multilayer-omics Reveal Sex- and Depot-Dependent Adipose Progenitor Cell Heterogeneity

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Cold-Responsive DPP4+ Progenitor Cells Facilitate Thermogenic Remodeling of Subcutaneous Adipose Tissue_isoproterenol treatment

Project description:The physiological adaptation to cold environmental temperatures involves the remodeling of energy-storing white adipose tissue (WAT) into an energy-burning thermogenic phenotype, characterized by the emergence of multi-locular beige adipocytes. To date, the full array of cold-responsive cells within WAT that mediate thermogenic remodeling remain undefined. Here, we demonstrate that distinct perivascular PDGFRb+ adipocyte precursor cell (APC) subpopulations are differentially sensitive to cold temperatures in vivo. One day of cold exposure elicits striking transcriptional changes in DPP4+ PDGFRb+ APCs, whereas committed DPP4- PDGFRb+ preadipocytes appear comparatively much less responsive. This adaptation includes beta-adrenergic receptor mediated induction in the expression of the pro-thermogenic cytokine, IL-33. DPP4+ PDGFRb+ cells represent the sole source of IL-33 within inguinal WAT of adult mice. Doxycycline-inducible deletion of Il33 in PDGFRb+ cells at the onset of cold exposure significantly compromises the thermogenic remodeling of WAT without directly impacting the differentiation capacity of APCs per se. Together, these studies reveal the presence of a cold-responsive progenitor cell subpopulation in adult WAT and highlight their ability to regulate tissue plasticity through the production of immunological factors.

2021-11-09 | GSE169672 | GEO

Cold-Responsive DPP4+ Progenitor Cells Facilitate Thermogenic Remodeling of Subcutaneous Adipose Tissue_p-CREB ChIP seq

2021-11-09 | GSE169669 | GEO

Cold-Responsive DPP4+ Progenitor Cells Facilitate Thermogenic Remodeling of Subcutaneous Adipose Tissue

2021-11-09 | GSE165974 | GEO

Mural Cell ZFP423 Controls Adipose Tissue Macrophage Accrual in Obesity [ChIP-seq]

Project description:Chronic low-grade visceral white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a specific subpopulation of adipose tissue perivascular (PDGFRb+) stromal cells, termed “fibro-inflammatory progenitors” (FIPs), activate pro-inflammatory signaling cascades shortly after the onset of high-fat diet feeding of mice and control the accumulation of pro-inflammatory macrophages in WAT. The activation of FIPs is mediated by the downregulation of ZFP423, identified here as a transcriptional co-regulator of NFkB. Biochemical analysis of ZFP423-protein complexes and ChIP-seq analysis reveal that ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NFkB by inducing a co-regulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRb+ cells suppresses inflammatory signaling in FIPs and attenuates macrophage accumulation within visceral WAT of obese mice. Conversely, inducible inactivation of Zfp423 in PDGFRb+ cells increases FIP activity, exacerbates adipose macrophage accrual, and promotes WAT dysfunction in obese mice. These studies implicate mural cells as sentinels and gatekeepers of adipose tissue inflammation in obesity.

2020-09-01 | GSE134868 | GEO

Perivascular Mesenchymal Cells Control Adipose Tissue Macrophage Accrual in Obesity

Project description:Chronic low-grade visceral white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a subpopulation of adipose tissue perivascular (PDGFRb+) cells, termed “fibro-inflammatory progenitors” (FIPs), activate pro-inflammatory signaling cascades shortly after the onset of high-fat diet feeding of mice and regulate pro-inflammatory macrophage accumulation in WAT in a TLR4-dependent manner. FIPs activation in obesity is mediated by the downregulation of ZFP423, identified here as a transcriptional co-regulator of NFkB. Biochemical analysis of ZFP423-protein complexes and ChIP-seq analysis reveal that ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NFkB by inducing a p300 to NuRD co-regulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRb+ cells suppresses inflammatory signaling in FIPs and attenuates metabolic inflammation of visceral WAT in obesity. Inducible inactivation of Zfp423 in PDGFRb+ cells increases FIP activity, exacerbates adipose macrophage accrual, and promotes WAT dysfunction. These studies implicate perivascular mesenchymal cells as important regulators of chronic adipose tissue inflammation in obesity and identify ZFP423 as a transcriptional break on NFkB signaling.

2020-09-01 | GSE151092 | GEO

Single cell RNA-sequencing of inguinal adipose tissue Pdgfrβ+ cells

Project description:We previously derived a doxycycline-inducible (Tet-On) lineage-tracing model that allows for the indelible labeling of Pdgfrb-expressing perivascular cells in adipose tissue of adult mice (PdgfrbrtTA; TRE-Cre; Rosa26RmT/mG; herein, MuralChaser mice). Prior to exposing animals to doxycyline, all cells within the stromal-vascular fraction (SVF) of adult inguinal WAT (iWAT) express membrane tdTomato from the Rosa26 locus. Following 9 days of exposure to doxycycline-containing chow diet, Cre-mediated excision of the loxP-flanked tdTomato cassette occurs in Pdgfrb-expressing cells, and membrane-bound GFP (mGFP) expression is constitutively activated. We set out to test the hypothesis that Pdgfrb-expressing perivascular cells in inguinal WAT of adult mice are heterogeneous, with subpopulations harboring functionally distinct phenotypes. To this end, we performed single cell RNA-sequencing of mGFP+ cells isolated from iWAT of lean (chow fed) 8 weeks-old male MuralChaser mice following 9 days of doxycycline exposure.

2020-09-01 | GSE144090 | GEO

Single cell RNA-sequencing of visceral adipose tissue Pdgfrβ+ cells

Project description:We previously derived a doxycycline-inducible (Tet-On) lineage-tracing model that allows for the indelible labeling of Pdgfrb-expressing perivascular cells in adipose tissue of adult mice (PdgfrbrtTA; TRE-Cre; Rosa26RmT/mG; herein, “MuralChaser mice”). Prior to exposing animals to doxycyline, all cells within the stromal-vascular fraction (SVF) of adult gonadal WAT (gWAT) express membrane tdTomato from the Rosa26 locus. Following 9 days of exposure to doxycycline-containing chow diet, Cre-mediated excision of the loxP-flanked tdTomato cassette occurs in Pdgfrb-expressing cells, and membrane-bound GFP (mGFP) expression is constitutively activated. We set out to test the hypothesis that Pdgfrb-expressing perivascular cells in gonadal visceral WAT of adult mice are heterogeneous, with subpopulations harboring functionally distinct phenotypes. To this end, we performed single cell RNA-sequencing of mGFP+ cells isolated from gWAT of lean (chow fed) 8 weeks-old male MuralChaser mice following 9 days of doxycycline exposure.

2018-09-01 | GSE111588 | GEO

PdgfrB signaling alters the beige adipogenic niche

Project description:Ageing beige adipose progenitor cells overexpress platelet derived growth factor receptor beta (PdgfrB) to prevent beige adipogenesis. Genetically deleting PdgfrB in restores beige adipocyte generation whereas activating PdgfrB in juvenile mice blocks beige fat formation.

2023-03-06 | GSE226695 | GEO

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