The Asp-Encoding Gene FBN1 Mediates Cold Adaptation in Sunite Sheep by Reprogramming Adipocyte Differentiation Towards Thermogenesis.

Sunite sheep are well-adapted to the cold Mongolian steppe, exhibiting robust metabolic flexibility in which adipose tissue contributes significantly to energy homeostasis. Proteomics analysis of scapular fat in Sunite sheep during winter and summer identified 432 upregulated and 493 downregulated differentially expressed proteins (DEPs). These DEPs were notably enriched in essential biological functions such as energy metabolism, lipogenesis, and thermogenesis. Furthermore, they exhibited significant enrichment of signaling pathways such as oxidative phosphorylation and fatty acid metabolism. Meanwhile, the precursor protein of asprosin (ASP),profibrillin-1 (pFBN1), showed a marked decrease during winter. Given that ASP had been demonstrated to exert metabolic regulatory effects promoting lipid synthesis and suppressing thermogenesis in model animals, it was hypothesized that the seasonal downregulation of pFBN1 might drive adaptive thermogenesis through ASP. Therefore, this study focused on functional validation of the ASP-encoding gene FBN1 (fibrillin-1). In Adipose-Derived Mesenchymal Stem Cells (ADMSCs), FBN1 was specifically downregulated through overexpressing of its regulatory factor miR-29b-1. The results indicated that downregulation of the FBN1 led to the inhibition of adipogenesis in ADMSCs. This was reflected by a reduction in the number of lipid droplets, a decrease in the expression of adipogenesis marker genes, and a significant drop in triglyceride levels. Furthermore, the reduction in FBN1 levels enhanced the thermogenic function of differentiated adipocytes derived from ADMSCs, as evidenced by enhanced expression of thermogenic marker genes, along with a notable rise in both uncoupling protein 1 (UCP1) and non-esterified fatty acid (NEFA) levels.