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PLoS One. 2016 Oct 27;11(10):e0163214. doi: 10.1371/journal.pone.0163214. eCollection 2016.

Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles.

Author information

1
Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
2
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
3
Mary Lyon Centre, MRC Harwell Institute, Harwell Campus, Oxford, United Kingdom.
4
MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxford, United Kingdom.
5
Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway.

Abstract

BACKGROUND:

Although reduced glutathione (rGSH) is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO) results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors, cysteine and glutamate. Plasma total cysteine (tCys) is positively associated with stearoyl-coenzyme A desaturase (SCD) activity and adiposity in humans and animal models.

OBJECTIVE:

To explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice.

DESIGN:

Male C3H/HeH mice aged 11 weeks were fed a high-fat diet with or without BSO in drinking water (30 mmol/L) for 8 weeks. Amino acid and fatty acid changes were assessed, as well as food consumption, energy expenditure, locomotor activity, body composition and liver vacuolation (steatosis).

RESULTS:

Despite higher food intake, BSO decreased particularly fat mass but also lean mass (both P<0.001), and prevented fatty liver vacuolation. Physical activity increased during the dark phase. BSO decreased plasma free fatty acids and enhanced insulin sensitivity. BSO did not alter liver rGSH, but decreased plasma total GSH (tGSH) and rGSH (by ~70%), and liver tGSH (by 82%). Glutamate accumulated in plasma and liver. Urine excretion of cysteine and its precursors was increased by BSO. tCys, rCys and cystine decreased in plasma (by 23-45%, P<0.001 for all), but were maintained in liver, at the expense of decreased taurine. Free and total plasma concentrations of the SCD products, oleic and palmitoleic acids were decreased (by 27-38%, P <0.001 for all).

CONCLUSION:

Counterintuitively, block of GSH synthesis decreases circulating tCys, raising the question of whether the BSO-induced obesity-resistance is linked to cysteine depletion. Cysteine-supplementation of BSO-treated mice is warranted to dissect the effects of cysteine and GSH depletion on energy metabolism.

Conflict of interest statement

AE and HR are inventors on a patent application for use of BSO as an anti-obesity agent. The authors confirm that this does not alter their adherence to PLOS ONE policies on sharing data and materials. All other authors reported no conflict of interest.

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