Cold-induced hepatic metabolic change links gluconeogenesis, lipid remodeling, and redox regulation in Xenopus laevis

Abstract

BackgroundEctothermic vertebrates exhibit substantial physiological plasticity in response to environmental temperature fluctuations. Among them, amphibians show particularly pronounced metabolic adjustments under cold conditions; however, the molecular mechanisms by which the liver adapts to low temperatures remain poorly understood. To address this gap, we investigated the hepatic transcriptional response to cold exposure in the African clawed frog (Xenopus laevis) using RNA sequencing (RNA-seq) and quantitative PCR. ResultsExposure to 5{degrees}C for five days in X. laevis resulted in pronounced hyperglycemia and extensive transcriptional reprogramming in the liver. RNA-seq analysis indicated that, relative to frogs maintained at 24{degrees}C, 2,392 genes were upregulated, whereas 2,031 genes were downregulated. Notably, genes associated with gluconeogenesis, such as foxo1, g6pc1, and pck1, exhibited significant upregulation, whereas genes related to glycolysis and glucose utilization, including gck, pfkm, and ldhb, were downregulated. Concurrently, cold exposure induced the expression of genes involved in fatty acid synthesis, desaturation, and cholesterol biosynthesis, such as srebf1, acaca, fasn, scd, fads2, srebf2, and hmgcr. Conversely, genes related to fatty acid {beta}-oxidation, including ppara, cpt1a, cpt1b, slc25a20, acadl, hadha, and hadhb, were significantly suppressed. In alignment with this pattern, multiple components of the mitochondrial electron transport chain and ATP synthesis machinery were also downregulated. Additionally, gene groups involved in antioxidant defenses, such as gpx4, gpx1, prdx2, prdx5, prdx6, and ferritin-related genes, were upregulated. Representative transcriptomic changes were validated using quantitative PCR analysis. ConclusionsExposure to cold temperatures induced coordinated metabolic reprogramming in the liver of X. laevis. This reprogramming was characterized by the activation of gluconeogenesis, suppression of glycolysis, fatty acid {beta}-oxidation, and oxidative phosphorylation, and induction of lipid and cholesterol biosynthetic pathways. These metabolic adjustments suggest that frogs acclimated to cold conditions adopt an energy-conserving metabolic strategy while sustaining glucose production and promoting lipid remodeling to adapt to low-temperature environments. These findings offer novel insights into the molecular mechanisms underlying cold adaptation in ectothermic vertebrates and underscore the pivotal role of the liver in managing transcriptional responses to cold stress.