TGF-β antagonism synergizes with PPARγ agonism to reduce fibrosis and enhance beige adipogenesis

作者：Young Jae Bahn, Yanling Wang, Pradeep K. Dagur, Nicholas Scott, Cheryl Cero, Kelly T Long, Nhuquynh Nguyen, Aaron M. Cypess, Sushil G. Rane · 发表于：Molecular Metabolism · 年份：2024 · DOI：10.1016/j.molmet.2024.102054 · 被引用次数：20 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Chronic Kidney Disease and Diabetes、Adipose Tissue and Metabolism

OBJECTIVES: Adipose tissue depots vary markedly in their ability to store and metabolize triglycerides, undergo beige adipogenesis and susceptibility to metabolic disease. The molecular mechanisms that underlie such heterogeneity are not entirely clear. Previously, we showed that TGF-β signaling suppresses beige adipogenesis via repressing the recruitment of dedicated beige progenitors. Here, we find that TGF-β signals dynamically regulate the balance between adipose tissue fibrosis and beige adipogenesis. METHODS: We investigated adipose tissue depot-specific differences in activation of TGF-β signaling in response to dietary challenge. RNA-seq and fluorescence activated cell sorting was performed to identify and characterize cells responding to changes in TGF-β signaling status. Mouse models, pharmacological strategies and human adipose tissue analyses were performed to further define the influence of TGF-β signaling on fibrosis and functional beige adipogenesis. RESULTS: Elevated basal and high-fat diet inducible activation of TGF-β/Smad3 signaling was observed in the visceral adipose tissue depot. Activation of TGF-β/Smad3 signaling was associated with increased adipose tissue fibrosis. RNA-seq combined with fluorescence-activated cell sorting of stromal vascular fraction of epididymal white adipose tissue depot resulted in identification of TGF-β/Smad3 regulated ITGA5+ fibrogenic progenitors. TGF-β/Smad3 signal inhibition, genetically or pharmacologically, reduced fibros...