Abstract

Obesity, an important risk factor for cardiovascular disease, promotes vascular oxidative stress. Considering that free testosterone levels remain within the reference range, especially in obese young men and that testosterone stimulates reactive oxygen species (ROS) generation, we sought to investigate whether testosterone interferes with obesity-associated oxidative stress and vascular dysfunction in male mice. We hypothesized that testosterone favors ROS accumulation and vascular dysfunction in high fat diet (HFD)-fed obese mice. We also questioned whether testosterone downregulates the nuclear factor E2–related factor 2 (Nrf2), one of the major cellular defense mechanisms against oxidative stimuli. Male C57Bl/6J mice were submitted to orchiectomy or sham-operation. Mice received either a control diet (CD) or HFD for 18 weeks. Vascular function was assessed in thoracic aortic rings and molecular mechanisms by which testosterone contributes to vascular dysfunction were determined. HFD reduced acetylcholine-induced vasodilation and increased vascular ROS generation in sham mice. Castration prevented these effects. Treatment of castrated mice fed either the CD or HFD with testosterone propionate decreased acetylcholine vasodilation. HFD decreased Nrf2 nuclear accumulation, events linked to decreased mRNA expression and activity of Nrf2-regulated enzymes (catalase, heme oxygenase-1, peroxiredoxin, and thioredoxin). These events were prevented in HFD-fed castrated mice. Bardoxolone, a Nrf2 activator, increased nuclear accumulation of Nrf2, decreased ROS generation and improved acetylcholine vasodilation in HFD-fed sham mice. In vitro, testosterone increased ROS generation and decreased Nrf2 nuclear accumulation. These effects were prevented in the presence of an androgen receptor antagonist, an inhibitor of gene transcription and an inhibitor of the pro-oxidant enzyme NOX-1. These results indicate that testosterone downregulates Nrf2, leading to oxidative stress and vascular dysfunction in HFD-fed obese young mice.

Highlights

  • Obesity is a major cause of morbidity and mortality in a large part of the world population (Andersson and Vasan, 2018; Csige et al, 2018)

  • The weight gain was higher in mice fed the high fat diet (HFD) as compared to the control diet (CD)-fed group

  • Castrated mice fed the CD and treated with testosterone propionate (5 mg/kg body weight) exhibited supraphysiological levels of testosterone, whereas castrated HFD-fed mice treated with the same dose of testosterone propionate (5 mg/kg body weight) exhibited testosterone levels similar to those observed in the sham group

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Summary

Introduction

Obesity is a major cause of morbidity and mortality in a large part of the world population (Andersson and Vasan, 2018; Csige et al, 2018). High birth weight is associated with an increased risk of obesity in adulthood (Yu et al, 2011; Zhao et al, 2012). Faster weight gain in children is associated with an increased risk of overweight and obesity later in life (Monteiro and Victora, 2005; Ong and Loos, 2006; Druet et al, 2012). Fat deposition in childhood and early adulthood accounts for increased cardiovascular risk (Nadeau et al, 2011; Caprio et al, 2020). It is unclear how body mass gain during the transition from early to middle adulthood, when most body mass gain occurs, relates to subsequent health consequences

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