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

Abstract

Aim Valuable studies have tested the role of UCP1 on body temperature maintenance in mice, and we sought to knockout Ucp1 in rats (Ucp1−/−) to provide insight into thermogenic mechanisms in larger mammals. Methods We used CRISPR/Cas9 technology to create Ucp1−/− 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. Results Ucp1−/− 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 than Ucp1−/− rats. Brown adipose tissue showed signs of decreased activity in Ucp1−/− 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. Conclusion Room 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 highlight Ucp1−/− rats as an attractive translational model for the study of thermogenesis.

Novel UCP1 knockout models broaden our understanding of mammalian non‐shivering thermogenesis

“…In this issue of Acta Physiologica, Warfel et al advance our knowledge on the physiological significance of brown adipose tissue (BAT) thermogenesis by creating a new uncoupling protein 1 (UCP1)-knockout rat model. 1 In mammals, adaptive non-shivering thermogenesis (NST) evolved in BAT to protect high body temperatures of small and newborn species in the cold and to accelerate arousal from hypothermic states, such as torpor and hibernation. 2 BAT is specialized for heat production by virtue of rich vascularization, capacity for rapid fatty acid mobilization of multilocular lipid droplets and high mitochondrial density.…”

“…8 Using Crispr-CAS, Warfel and colleagues generated the UCP1 KO rat, which is so far only the second species with an artificial genetic UCP1 inactivation. 1 The value of yet another rodent model does not transpire at first sight, but the thermoregulatory differences between mice and rats are significant. While mice would readily go into a torpid state upon fasting to save energy, rats prefer to maintain high body temperatures and continue foraging.…”

“…In this issue of Acta Physiologica , Warfel et al advance our knowledge on the physiological significance of brown adipose tissue (BAT) thermogenesis by creating a new uncoupling protein 1 (UCP1)‐knockout rat model 1 …”

“…Using Crispr‐CAS, Warfel and colleagues generated the UCP1 KO rat, which is so far only the second species with an artificial genetic UCP1 inactivation 1 . The value of yet another rodent model does not transpire at first sight, but the thermoregulatory differences between mice and rats are significant.…”

Relativistic aspects of physiology: Expanding our understanding of conventional control loops

“…All of them represent the need for considering a unique set of additional dimensions when interpreting the function of our physiological control loops: 1 | THERM ORE GUL ATION Thermoregulation refers to the physiological process of maintaining a stable internal body temperature across varying conditions. 21 The importance of precise thermoregulation becomes critical during specialized scenarios like cardiac surgery conducted under deep hypothermia, where inaccurate temperature readings can have severe consequences. Traditional approaches to thermoregulation, which often rely on a single core body temperature measured at conventional sites like the rectum or bladder, may not accurately reflect temperature variations in critical organs like the brain or the heart.…”