NOX2 deficiency exacerbates diet-induced obesity and impairs molecular training adaptations in skeletal muscle
Carlos Henriquez-Olguin,
Roberto Meneses-Valdes,
Steffen H. Raun,
Samantha Gallero,
Jonas R. Knudsen,
Zhencheng Li,
Jingwen Li,
Lykke Sylow,
Enrique Jaimovich,
Thomas E. Jensen
Affiliations
Carlos Henriquez-Olguin
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark; Exercise Science Laboratory, Faculty of Medicine, Universidad Finis Terrae, Av. Pedro de Valdivia 1509, Santiago, Chile; Corresponding author. The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Universitetsparken 13, 2100, Denmark.
Roberto Meneses-Valdes
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark; Center for Exercise, Metabolism and Cancer, ICBM, Universidad de Chile, 8380453, Santiago, Chile
Steffen H. Raun
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 3 Blegdamsvej, Copenhagen N, Denmark
Samantha Gallero
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark
Jonas R. Knudsen
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark
Zhencheng Li
College of Physical Education, Chongqing University, Chongqing, 400044, CN, China
Jingwen Li
School of Medicine and Nursing, Huzhou University, Huzhou, 313000, CN, China
Lykke Sylow
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 3 Blegdamsvej, Copenhagen N, Denmark
Enrique Jaimovich
Center for Exercise, Metabolism and Cancer, ICBM, Universidad de Chile, 8380453, Santiago, Chile
Thomas E. Jensen
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise, and Sports, University of Copenhagen, August Krogh Building, Universitetsparken 13, 2100, Copenhagen, Denmark; Corresponding author.
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.
