Glutaredoxin 1 controls monocyte reprogramming during nutrient stress and protects mice against obesity and atherosclerosis in a sex-specific manner

Yong Joo Ahn, Luxi Wang, Sina Tavakoli, Huynh Nga Nguyen, John D. Short and Reto Asmis ()
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Yong Joo Ahn: Wake Forest School of Medicine
Luxi Wang: Wake Forest School of Medicine
Sina Tavakoli: University of Pittsburgh
Huynh Nga Nguyen: University of Texas Health Science Center at San Antonio
John D. Short: University of Texas Health Science Center at San Antonio
Reto Asmis: Wake Forest School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract High-calorie diet-induced nutrient stress promotes thiol oxidative stress and the reprogramming of blood monocytes, giving rise to dysregulated, obesogenic, proatherogenic monocyte-derived macrophages. We report that in chow-fed, reproductively senescent female mice but not in age-matched male mice, deficiency in the thiol transferase glutaredoxin 1 (Grx1) promotes dysregulated macrophage phenotypes as well as rapid weight gain and atherogenesis. Grx1 deficiency derepresses distinct expression patterns of reactive oxygen species and reactive nitrogen species generators in male versus female macrophages, poising female but not male macrophages for increased peroxynitrate production. Hematopoietic Grx1 deficiency recapitulates this sexual dimorphism in high-calorie diet-fed LDLR-/- mice, whereas macrophage-restricted overexpression of Grx1 eliminates the sex differences unmasked by high-calorie diet-feeding and protects both males and females against atherogenesis. We conclude that loss of monocytic Grx1 activity disrupts the immunometabolic balance in mice and derepresses sexually dimorphic oxidative stress responses in macrophages. This mechanism may contribute to the sex differences reported in cardiovascular disease and obesity in humans.

Date: 2022
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DOI: 10.1038/s41467-022-28433-2

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