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SOX4 Drives a Cancer-Associated Fibroblast-like Transition in Adipose Stromal Cells to Promote Metabolic Disease

ABSTRACT: Adipose tissue dysfunction drives metabolic disease in obesity and is characterized by impaired adipogenesis, chronic inflammation, and fibrosis. Here, we define a pathogenic cancer-associated fibroblast-like (CAF-like) stromal population that accumulates in visceral adipose tissue during obesity under the control of the transcription factor SOX4. Obesity and TGFβ signaling induce SOX4 in mesenchymal stromal cells (MSCs), where it promotes a CAF-like transcriptional program while suppressing adipogenic differentiation. SOX4 activation in mouse MSCs exacerbated adipose inflammation, fibrosis, and glucose intolerance independently of adiposity. Conversely, Sox4 deletion reduced adipose immune cell accumulation and improved glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector of CAF-like cells. MDK inhibition in obese mice reduced adipose tissue inflammation and improved metabolic function, whereas MDK activation promoted inflammatory remodeling of adipose tissue. In human adipose tissue, SOX4 and MDK expression were elevated in type 2 diabetes, and SOX4 activated a CAF-like transcriptional program in human MSCs. Overall, these findings identify a TGFβ-SOX4-MDK axis that drives pathogenic stromal reprogramming in adipose tissue and contributes to metabolic disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE333670 | GEO | 2026/05/28

REPOSITORIES: GEO

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Project description:Obesity is a health problem characterized by large expansion of adipose tissue. During this expansion, genotoxic stressors can be accumulated and negatively affect the Mesenchymal Stem Cells (MSCs) of adipose tissue. Due to the oxidative stress generated by these genotoxic stressors, senescence phenotype might be observed in adipose tissue MSCs. Senescent MSCs lose their proliferations and differentiation properties and secrete senescence-associated molecules to their niche thus triggering senescence for the rest of the tissue. Accumulation of senescent cells in adipose tissue results in decreased tissue regeneration and functional impairment not only in the close vicinity but also in the other tissues. Here we hypothesized that declined tissue regeneration might be associated with loss of stemness in MSCs population. We analyzed the expression of several stemness genes in adipose tissue MSCs of high-fat diet and normal diet mice models. Since the MSCs population covers a small percentage of the pluripotent stem cells, a role in proliferation and tissue regeneration, we measured the percentage of these cells via TRA-1-60 surface antigen. Additionally, by conducting a shotgun proteomic approach using LC-MS/MS, whole cell proteome of the adipose tissue MSCs of high-fat diet and normal diet mice were analyzed and identified proteins were evaluated via Gene Ontology and PPI network analysis. MSCs of obese mice showed senescent phenotype and altered cell cycle distribution due to a hostile environment with oxidative stress in adipose tissue where they reside. Additionally, the number of pluripotent markers expressing cells declined in the MSC population of the high-fat diet mice. Gene expression analysis evidenced the loss of stemness with a decrease in the expression of stemness-associated genes. Of the proteomic comparison of the normal and the high-fat diet group, MSCs revealed that stemness-associated molecules were decreased while inflammation and senescence-associated phenotypes emerged in obese mice MSCs. Our results showed us that the MSCs of adipose tissue may lose their stemness properties due to obesity-associated stress conditions.

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SOX4 Drives a Cancer-Associated Fibroblast-like Transition in Adipose Stromal Cells to Promote Metabolic Disease

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