Abstract
Chronic caloric excess induced metaflammation suppresses adipose tissue resident mesenchymal stromal cell (MSC) differentiation into functional adipocytes, contributing to various metabolic disorders. The molecular mechanisms of MSC multipotency regulation under such conditions is not well understood. In this study, a long-term high-fat diet fed mouse model showed that pro-inflammatory cytokine interferon-gamma (IFNγ) is a central regulator of visceral adipose hyperplasia. Chronic IFNγ exposure activated STAT5 played crucial roles in restricting MSC adipogenic potential. Further genetic and pharmacological studies using human and mouse visceral MSCs revealed that chronic inflammation constitutively activates IFNγ stimulated STAT5 and TGFβ stimulated Smad3 transcription factors by synergistic actions of multiple signaling pathways. STAT5 physically interacts with Smad4 of Smad3-Smad4 complex to inhibit the expression of selective adipogenic proteins including PPARγ and C-EBPδ, in favor of exerting sustained anti-inflammatory functions from MSCs. Overall, our study delineates a central regulatory mechanism of MSC multipotency and immune response.
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