Nrf2 plays a critical role in the metabolic response during and after spaceflight

Akira Uruno,Ristumi Saito,Takafumi Suzuki,Mikiko Suzuki,Masaki Shimizu ,Thomas W Kensler,Tomohiro Nakamura,Naomi Matsukawa,Risa Okada,Akihito Otsuki,Akane Yumoto,Y Tomioka ,Norio Suzuki,Ritsuko Shimizu,Fumiki Katsuoka,Eiji Hishinuma,Takahiro Yamazaki,S Koshiba ,Keiko Taguchi,Dai Shiba,Daisuke Saigusa,Masayuki Yamamoto

doi:10.1038/s42003-021-02904-6

Abstract

Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

Highlights

Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf[2] (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses
We analysed the levels of ketone bodies in inferior vena cava (IVC) blood samples from individual mice at R + 2 using NMR to determine whether the data from mouse FL04 needed to be excluded
An intriguing observation is that the increased levels of cholesteryl esters, glycerophospholipids and sphingolipids in L +18 FL-WT mice were markedly attenuated in FL-KO mice. These results indicate that plasma levels of cholesteryl esters, glycerophospholipids and sphingolipids were elevated during spaceflight and that Nrf[2] contributed to the increased levels of these lipids in the L+18 samples

Summary

Introduction

Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf[2] (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf[2] knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf[2] plays critical roles in these responses. In the course of initial analyses, we found that Nrf[2] activity is induced by space travel and that both the weight and lipid droplet size of epididymal white adipose tissue (eWAT) are increased in WT mice after spaceflight. Nrf[2] deletion represses eWAT weight gain and lipid droplet enlargement, indicating the contribution of Nrf[2] to the metabolic responses in mice exposed to spaceflight

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