Rats lackingUcp1present a novel translational tool for the investigation of thermogenic adaptation during cold challenge

Abstract

AbstractAimValuable studies have tested the role of UCP1 on body temperature maintenance in mice, and we sought to knockoutUcp1in rats (Ucp1−/−) to provide insight into thermogenic mechanisms in larger mammals.MethodsWe used CRISPR/Cas9 technology to createUcp1−/−rats. Body weight and adiposity were measured, and rats were subjected to indirect calorimetry. Rats were maintained at room temperature or exposed to 4°C for either 24 h or 14 days. Analyses of brown and white adipose tissue and skeletal muscle were conducted via histology, western blot comparison of oxidative phosphorylation proteins, and qPCR to compare mitochondrial DNA levels and mRNA expression profiles. RNA‐seq was performed in skeletal muscle.ResultsUcp1−/−rats withstood 4°C for 14 days, but core temperature steadily declined. All rats lost body weight after 14 days at 4°C, but controls increased food intake more robustly thanUcp1−/−rats. Brown adipose tissue showed signs of decreased activity inUcp1−/−rats, while mitochondrial lipid metabolism markers in white adipose tissue and skeletal muscle were increased.Ucp1−/−rats displayed more visible shivering and energy expenditure than controls at 4°C. Skeletal muscle transcriptomics showed more differences between genotypes at 23°C than at 4°C.ConclusionRoom temperature presented sufficient cold stress to rats lacking UCP1 to activate compensatory thermogenic mechanisms in skeletal muscle, which were only activated in control rats following exposure to 4°C. These results provide novel insight into thermogenic responses to UCP1 deficiency; and highlightUcp1−/−rats as an attractive translational model for the study of thermogenesis.