Nrf2 contributes to the weight gain of mice during space travel

Abstract

Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice

“…The body weight of adult Nrf2 KO mice was lower compared to WT mice fed a normal diet [ 37 ]. Nrf2 was involved in weight gain in male mice during space travel by maintaining homeostasis of white adipose tissue [ 38 ]. Decreased expression of peroxisome proliferator-activated receptor γ due to Nrf2 deficiency prevented weight gain and obesity from a high fat diet and environmental stress caused by space travel [ 37 , 38 ].…”

“…Nrf2 was involved in weight gain in male mice during space travel by maintaining homeostasis of white adipose tissue [ 38 ]. Decreased expression of peroxisome proliferator-activated receptor γ due to Nrf2 deficiency prevented weight gain and obesity from a high fat diet and environmental stress caused by space travel [ 37 , 38 ]. In our previous study, the body weight of male control mice was not affected by Nrf2 KO at week 16 [ 24 ].…”

Keap1/Nrf2 Signaling Pathway

“…Nuclear factor, erythroid 2-like transcription factor 2 (Nrf2) and its cytoplasmic inhibitor, kelch-like ECH-associated protein 1 (Keap1), comprise a redox-responsive endogenous antioxidant defense module that orchestrates the expression of cytoprotective genes to maintain homeostasis [ 1 ]. Currently in its third decade, Keap1/Nrf2-related research continues to achieve landmarks, such as the recent demonstration of the role of Nrf2 in weight gain during space travel [ 2 ]. While much is already known about the regulation and functioning of the Keap1/Nrf2 pathway, basic research continues to reveal new insights; examples from the present Special Issue include distinct and overlapping roles in gene expression regulation with related cap’n’collar transcription factors Nrf1 and Nrf3 [ 3 ], as well as the connection of Nrf2 to cellular organelles with important emerging roles such as primary cilia [ 4 ].…”

Biomimetics provides lessons from nature for contemporary ways to improve human health

“…A protective role for Nrf2 in the aging process is further supported by low Nrf2 expression in children with extreme premature vascular ageing due to Hutchinson-Gilford Progeria syndrome (108). Additionally, a recent study conducted in Nrf2 k/o mice sent into space, has revealed that Nrf2-deficiency induces ageing-like changes in plasma metabolites and weight gain (109). While important lessons on protective mechanisms in ageing can be learned from long-lived fish with negligible senescence, such as the Greenland shark (>400 years) and Bowhead whale (>200 years), short-lived fish, such as killifish (13 weeks) have emerged as an important natural animal models for ageing research (105).…”