title: Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles.
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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
authors: Amany K
authors: AK
authors: Elshorbagy
authors: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors: Fredrik
authors: F
authors: Jernerén
authors: Mary Lyon Centre, MRC Harwell Institute, Harwell Campus, Oxford, United Kingdom.
authors: Cheryl L
authors: CL
authors: Scudamore
authors: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxford, United Kingdom.
authors: Fiona
authors: F
authors: McMurray
authors: Mary Lyon Centre, MRC Harwell Institute, Harwell Campus, Oxford, United Kingdom.
authors: Heather
authors: H
authors: Cater
authors: Mary Lyon Centre, MRC Harwell Institute, Harwell Campus, Oxford, United Kingdom.
authors: Tertius
authors: T
authors: Hough
authors: MRC Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxford, United Kingdom.
authors: Roger
authors: R
authors: Cox
authors: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.|Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway.
authors: Helga
authors: H
authors: Refsum
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D019328:Buthionine Sulfoximine / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D005978:Glutathione / Q000172:deficiency* / Q000652:urine; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008124:Locomotion; D008297:Male; D051379:Mice; D010641:Phenotype; D013438:Sulfhydryl Compounds / Q000097:blood / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D007328:Insulin; D013438:Sulfhydryl Compounds; D019328:Buthionine Sulfoximine; D005978:Glutathione