In-depth analysis of obesity-associated changes in adipose tissue-derived mesenchymal stromal/stem cells and primary cilia function

TL;DR

Obesity affects fat-derived stem cells by altering their genes and impairing tiny cell structures called primary cilia, which may reduce their regenerative abilities.

Contribution

The study reveals that obesity impairs primary cilia function in ASCs and identifies ADCY3 as a potential therapeutic target.

Findings

Obesity downregulates RFX2 and ADCY3 genes important for ciliary biogenesis in ASCs.

Pharmacological activation of ADCY3 restores primary cilium length and improves cell motility.

Obesity-related ASC dysfunction is linked to impaired primary cilia and reduced regenerative capacity.

Abstract

Adipose tissue-derived mesenchymal stromal/stem cells (ASCs) possess regenerative potential. Obesity induces a pro-inflammatory environment that compromises their function. Here we investigate how obesity affects ASC biology, focusing on primary cilia. Our data show that obesity alters ASC gene expression, particularly in pathways related to the extracellular matrix, transforming growth factor-β (TGFβ) signaling, cell motility, and differentiation. The gene levels of regulatory factor X2 (RFX2) and adenylate cyclase 3 (ADCY3), important for ciliary biogenesis, are downregulated in obese ASCs. TGFβ treatment significantly decreases the expression of RFX2 and ADCY3 in lean ASCs. Knockdown of ADCY3 reduces primary cilium length, whereas pharmacological activation restores it and improves cell motility. These results suggest that obesity impairs ASC ciliary function, contributing to defective adipogenesis and reduced regenerative capacity. Restoring ADCY3 activity partially rescues ciliary integrity and cellular function, highlighting the role of primary cilia in ASC dysfunction and offering potential therapeutic targets for obesity-related disorders.

Obesity alters the transcriptome profile of adipose-tissue derived mesenchymal stem cells (ASCs) and impairs ciliary biogenesis. Restoring adenylate cyclase 3 activity partially rescues ciliary integrity and function of ASCs from donors with obesity.

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