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TGF-b/Smad3 inhibition synergizes with PPARg agonism to reduce fibrosis and enhance functional beige adipogenesis

ABSTRACT: Adipose tissue depots vary markedly in their ability to store and metabolize triglycerides, undergo beige adipogenesis and be susceptibile to metabolic disease. The molecular mechanisms that underlie such heterogeneity are not entirely clear. Previously, we showed that TGF-b signaling regulates the browning of white adipose tissue via recruitment of dedicated beige progenitors. Here, we find that TGF-b signals dynamically regulate the balance between adipose tissue fibrosis and beige adipogenesis. Elevated basal and high-fat diet inducible activation of TGF-b/Smad3 signaling was observed in the visceral (epididymal) adipose tissue depot. Activation of TGF-b/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-b/Smad3 regulated ITGA5+ fibrogenic progenitors. TGF-b/Smad3 signal inhibition, genetically or pharmacologically, reduced fibrosis and increased functional beige adipogenesis. TGF-b/Smad3 antagonized the beneficial effects of PPARγ , activation whereas TGF-b receptor 1 inhibition synergized with actions of rosiglitazone, a PPARγ agonist, to dampen fibrosis and promote beige adipogenesis. There was a positive correlation between TGF-b activation and levels of fibrosis marker, ITGA5, in human adipose tissue samples , with visceral (omental) adipose tissue depot exhibiting higher fibrosis potential than subcutaneous or brown adipose tissue depots. Taken together, out data provide TGF-b/Smad3 signaling operates at the nexus of adipose tissue fibrosis and functional beige adipogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE268791 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:*Background: Adipocytes mainly function as energy storage and endocrine cells. The amount and distribution of fat are important factor that influence the meat quality in the beef industry. Fat depot can be found around internal organ (ometal), beneath the skin (subcutaneous), and between muscles (intramuscular). Different adipose depot showed the biological and genetic difference depending on their location. This inter-depot variation might be influenced by the inherent genetic programing for development of adipose depots. In this study, we used RNA-seq data to investigate the difference in transcriptome of various adipose depots in Hanwoo. *Results: Using RNA-seq, we identified 5797, 2156, and 5455 DEGs in the comparison between OI, OS, and IS respectively (FDR<0.01) and found 853, 48, and 979 DEGs specific to subcutaneous, intramuscular and omental fat respectively. DEGs in intramuscular fat were highly enriched the metabolism related pathways compared to other fat depots. DEGs specific to the omental fat is significantly enriched in PPAR signaling pathway and cell-junction related pathway. In subcutaneous fat, cytokine-cytokine receptor interaction with chemokines (CXC and CC subfamily) was the most significantly enriched the pathways. Interestingly, melanogenesis pathway was associated with the subcutaneous depot. Even though the adipose tissues shared the same pathways for adipocyte differentiation, the regulation of genes were different based on the depot. *Conclusions: We comparatively analyzed the transcripome profile from different adipose tissues using NGS and identified DEGs between adipose depot and specific to depot in Hanwoo animals. The functional annotation analysis of DEGs found that transcriptome profile difference in various adipose tissue of intramuscular, subcutaneous, and ometal fat. whole mRNA sequencing profiles of nine Korean native cattle (nine profiles of omental fat tissue, nine profiles of intramuscular fat tissue, nine profiles of subcutaneous fat tissue and eight profiles of muscle tissue)

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TGF-b/Smad3 inhibition synergizes with PPARg agonism to reduce fibrosis and enhance functional beige adipogenesis

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