MFAP5 enhances the cold resistance of piglets by promoting the transition of adipocyte progenitor cells to fibroblast lineage

Although pigs lack classical brown adipose tissue, several studies have demonstrated that porcine adipocytes possess the capacity to undergo thermogenesis through UCP1-independent mechanisms. However, the developmental processes and regulatory mechanisms underlying these thermogenic adipocytes remain poorly characterized. Here, we found that dorsal subcutaneous adipose tissues (subWATs) in pigs exhibits significant thermogenic potential under cold stress. Notably, we observed substantial cold-induced structural remodeling in dorsal subWATs, characterized by increased fibrotic deposition. An integrated analysis of snRNA-seq and RNA-seq data on dorsal subWATs identified MFAP5, which encodes a microfibril-associated glycoprotein in the extracellular matrix, as a potential regulator of the cold-induced plasticity of dorsal subWATs. Both MFAP5 overexpression and MFAP5-conditioned medium (MFAP5-CM) not only inhibited preadipocyte differentiation into adipocytes but also promoted their commitment to non-adipogenic fibrogenic lineages. Furthermore, MFAP5 treatments significantly enhanced the mitochondrial biogenesis of these fibrogenic cells. Mechanistic investigations showed that these phenotypic alterations are predominantly mediated through the Hippo signaling pathway. In summary, our findings elucidate the pivotal role of MFAP5 in regulating adipocyte development following cold exposure, thus providing crucial insights into the molecular mechanisms underlying porcine adaptation to cold stress.