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

Abstract

BackgroundAlthough 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.ObjectiveTo explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice.DesignMale 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).ResultsDespite 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).ConclusionCounterintuitively, 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.

Fatty acids suppress the steroidogenesis of the MA-10 mouse Leydig cell line by downregulating CYP11A1 and inhibiting late-stage autophagy

“…Additionally, to test the capacity of steroidogenesis, MA-10 cells were treated with or without 50 µM 8-Br-cAMP for 4 h. To mimic the plasma FFAs of mice during obesity, a 0.8- to 1.2-mM FA mixture containing the same amount of OA and PA was added to the culture medium. The FA concentration and composition were similar to the plasma profile of obese mice 32 . In our MA-10 model, the 0.8-mM FA mixture significantly induced lipid accumulation but had no effects on progesterone (P4) production in both the basal and 8-Br-cAMP-stimulated states (Fig.…”

Combining Dietary Sulfur Amino Acid Restriction with Polyunsaturated Fatty Acid Intake in Humans: A Randomized Controlled Pilot Trial

“…The diet or drug-induced lowering of plasma tCys concentrations has been associated with beneficial changes in body composition in animal models [19,20,21,22], but the mechanisms through which cysteine promotes obesity is presently unknown. One possible mechanism may be by influencing the fatty acid desaturase enzyme stearoyl–CoA desaturase-1 (SCD1).…”

Glycine Increases Insulin Sensitivity and Glutathione Biosynthesis and Protects against Oxidative Stress in a Model of Sucrose‐Induced Insulin Resistance

“…Glutathione deficiency and its relationship with obesity and insulin resistance is controversial. Recently, depletion of glutathione by pharmacological inhibition or by genetic deletion of γ -GCS was reported to protect mice from diet-induced obesity and insulin resistance [ 5 , 6 ]. On the other hand, glycine and cysteine, when supplemented together to the diet of aged and diabetic patients, have been described to increase glutathione bioavailability, reduce oxidative stress, and enhance glucose metabolism [ 7 , 8 ].…”