Chronic cold stress promotes inflammation and ER stress via inhibiting GLP-1R signaling, and exacerbates the risk of ferroptosis in the liver and pancreas

The cold climates in autumn and winter threatens human health. The aim of this study was to reveal the effects of prolonged cold exposure on the liver and pancreas based on GLP-1R signaling, oxidative stress, endoplasmic reticulum (ER) stress and ferroptosis by Yorkshire pig models. Yorkshire pigs were divided into the control group and chronic cold stress (CCS) group. The results showed that CCS induced oxidative stress injury, activated Nrf2 pathway and inhibited the expression of GLP-1R in the liver and pancreas (P < 0.05). The toll-like receptor 4 (TLR4) pathway was activated in the liver and pancreas, accompanied by the enrichment of IL-1β and TNF-α during CCS (P < 0.05). Moreover, the kinase RNA-like endoplasmic reticulum kinase (PERK), inositol requiring kinase 1 (IRE1), X-box-binding protein 1 (XBP1) and eukaryotic initiation factor 2α (eIF2α) expression in the liver and pancreas was up-regulated during CCS (P < 0.05). In addition, CCS promoted the prostaglandin-endoperoxide synthase 2 (PTGS2) expression and inhibited the ferritin H (FtH) expression in the liver. Summarily, CCS promotes inflammation, ER stress and apoptosis by inhibiting the GLP-1R signaling and inducing oxidative stress, and exacerbates the risk of ferroptosis in the liver and pancreas.