Modulating Visceral Adipose Tissue Immunometabolism: GLP-1RA Semaglutide’s Impact on Immune–Stromal Networks

Abstract

Obesity and type 2 diabetes (T2D) are major metabolic diseases characterized by chronic inflammation and dysregulated adipose tissue homeostasis. Visceral adipose tissue (VAT) serves as an immunological organ that integrates metabolic and inflammatory signals through dynamic interactions between immune and stromal cells. Regulatory T cells (Tregs) are enriched in lean VAT and contribute to metabolic homeostasis by suppressing inflammation and regulating the IL-33-expressing VAT mesenchymal stromal cells (VmSCs). Emerging evidence suggests that stromal cells establish specialized immunoregulatory niches that sustain Treg populations and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for T2D with improved metabolic outcomes, yet the mechanisms governing stromal–immune crosstalk and GLP-1RA effects on VAT microenvironment remain poorly understood. In this study, we investigated how semaglutide alters the immune and stromal compartments within VAT and examined the role of the IL-33–VmSC–Treg axis in mediating these effects. We found that semaglutide increases IL-33+ VmSCs proliferation and modulation of VAT ST2+ Tregs at cellular levels. In addition, semaglutide shifted adipogenic stromal populations by reducing VmSC5 and restoring VmSC4 in vivo, with stronger effects under long-term high-fat diet. Despite these changes, direct effects of semaglutide on Tregs were minimal in vitro, suggesting that GLP-1RA–mediated modulation of VAT immunity occurs indirectly through the stromal niche. Together, these findings support a model in which stromal cells and Tregs form a dynamic regulatory circuit that is reshaped by metabolic interventions. Together, this work highlights the importance of the immune-stromal axis in VAT regulation, provides new insight into mechanisms linking metabolism and immune regulation in VAT, and suggests potential novel therapeutic strategies for metabolic diseases.