Dataset Information

Regulating the Cell Differentiation Trajectory of Progenitor Cells in Adipose Tissue Fibrosis

ABSTRACT: Adipose fibrosis signifies pathological remodeling of white adipose tissue (WAT) associated with insulin resistance, diabetes, and cardiovascular disease. Matrix Gla protein (MGP) balances bone morphogenic protein (BMP) and transforming growth factors (TGF) β signaling but has an unclear role in WAT. Our study showed that Mgp gene deletion promotes fibrosis and impairs adipogenesis in mice with global or platelet-derived growth factor receptor α (Pdgfrα)-Cre-mediated Mgp deletion in APCs. Single cell RNA sequencing showed two new adipose-derived stem cells (ASC) populations, ASC1 and ASC4, emerging after Mgp deletion. Trajectory analysis found that ASC1 and ASC4 were derived from ASC2, which normally undergo adipogenesis but instead had diverted to fibrogenic differentiation. All three ASCs expressed Pdgfrα and dipeptidyl peptidase 4 (Dpp4). Signaling studies in mice with Pdgfrα-Cre-mediated Mgp deletion using SB431542 or sitagliptin reduced TGFβ activity, the size of the PDGFRα+, DPP4+ cell population and fibrogenesis. Dysregulation of PDGFRα+, DPP4+ cells may signal early adipose fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE296596 | GEO | 2025/09/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

Dataset Information

Regulating the Cell Differentiation Trajectory of Progenitor Cells in Adipose Tissue Fibrosis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets