NOX2 deficiency exacerbates diet-induced obesity and impairs molecular training adaptations in skeletal muscle

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The production of reactive oxygen species (ROS) by NADPH oxidase (NOX) 2 has been linked to both insulin resistance and exercise training adaptations in skeletal muscle. This study explores the previously unexamined role of NOX2 in the interplay between diet-induced insulin resistance and exercise training (ET). Using a mouse model that harbors a point mutation in the essential NOX2 regulatory subunit, p47phox (Ncf1*), we investigated the impact of this mutation on various metabolic adaptations. Wild-type (WT) and Ncf1* mice were assigned to three groups: chow diet, 60% energy fat diet (HFD), and HFD with access to running wheels (HFD + E). After a 16-week intervention, a comprehensive phenotypic assessment was performed, including body composition, glucose tolerance, energy intake, muscle insulin signaling, redox-related proteins, and mitochondrial adaptations. The results revealed that NOX2 deficiency exacerbated the impact of HFD on body weight, body composition, and glucose intolerance. Moreover, in Ncf1* mice, ET did not improve glucose tolerance or increase muscle cross-sectional area. ET normalized body fat independently of genotype. The lack of NOX2 activity during ET reduced several metabolic adaptations in skeletal muscle, including insulin signaling and expression of Hexokinase II and oxidative phosphorylation complexes. In conclusion, these findings suggest that NOX2 mediates key beneficial effects of exercise training in the context of diet-induced obesity.

OriginalsprogEngelsk
Artikelnummer102842
TidsskriftRedox Biology
Vol/bind65
Antal sider12
ISSN2213-2317
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The authors extend their gratitude to Rikard Holmdahl of the Karolinska Institute in Sweden for providing the Ncf1* mice and to Betina Bolmgren from the August Krogh Section for Molecular Physiology, NEXS, Faculty of Science, University of Copenhagen, for her expert technical assistance. CH–O and JRK were generously supported by grants from the Danish Diabetes Academy, funded by the Novo Nordisk Foundation (Grant no. NNF17SA0031406). JRK was supported by an International Postdoc Grant from the Independent Research Fund Denmark (#9058-00047B). JL was funded by a Chinese Scholarship Council Ph.D. stipend (no. 201707940001). Project running costs were covered by the Independent Research Fund Denmark (TEJ, Grant no. 9039-00029B) and the Lundbeck Foundation Ascending Investigator Grant (TEJ, no. R313-2019-643). The imaging data were collected at the Core Facility for Integrated Microscopy at the University of Copenhagen in Denmark.

Funding Information:
The authors extend their gratitude to Rikard Holmdahl of the Karolinska Institute in Sweden for providing the Ncf1* mice and to Betina Bolmgren from the August Krogh Section for Molecular Physiology, NEXS, Faculty of Science, University of Copenhagen, for her expert technical assistance. CH–O and JRK were generously supported by grants from the Danish Diabetes Academy , funded by the Novo Nordisk Foundation (Grant no. NNF17SA0031406 ). JRK was supported by an International Postdoc Grant from the Independent Research Fund Denmark ( #9058-00047B ). JL was funded by a Chinese Scholarship Council Ph.D. stipend (no. 201707940001 ). Project running costs were covered by the Independent Research Fund Denmark (TEJ, Grant no. 9039-00029B ) and the Lundbeck Foundation Ascending Investigator Grant (TEJ, no. R313-2019-643 ). The imaging data were collected at the Core Facility for Integrated Microscopy at the University of Copenhagen in Denmark.

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© 2023 The Authors

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