Cold Stress-Induced Adipose Tissue Remodeling in Min pigs: Involvement of the ADRB3-ERK Axis, Autophagy, and Inflammatory Pathways

Abstract

Cold stress induces adaptive remodeling of adipose tissue, yet the coordinated molecular network, particularly the interplay between upstream signaling pathways and downstream cellular responses, remains incompletely understood. This study investigated whether cold stress regulates adipose tissue beiging, apoptosis, and systemic metabolic remodeling through autophagy and inflammation mediated by the β3-adrenergic receptor (ADRB3)-extracellular signal-regulated kinase (ERK) signaling axis. The results demonstrated that cold stress significantly increased energy expenditure and markedly improved glucose tolerance and insulin sensitivity in Min pigs. In subcutaneous adipose tissue, cold stress induced pronounced beiging, as evidenced by reduced adipocyte size, the presence of multilocular lipid droplets, and upregulation of beige adipocyte marker genes, accompanied by increased preadipocyte apoptosis. Transcriptomic analysis revealed significant enrichment of pathways related to autophagy and lipolysis, with inflammation (notably the TNF signaling pathway) also identified as a potential contributing process. Mechanistically, cold stress activated the ADRB3-ERK signaling axis, leading to enhanced autophagic activity, and inflammation-related genes were also upregulated, suggesting that inflammation may serve as a candidate process cooperating with autophagy. In conclusion, this study reveals a novel molecular mechanism whereby cold stress activates the ADRB3-ERK signaling axis to stimulate autophagy, with inflammation potentially cooperating as a candidate process, thereby driving adipose tissue beiging, apoptosis, and systemic metabolic remodeling.