Glutathione Decrement Drives Thermogenic Program In Adipose Cells

Abstract

Adipose tissue metabolically adapts to external stimuli. We demonstrate that the induction of the thermogenic program in white adipocytes, through cold exposure in mice or in vitro adrenergic stimulation, is accompanied by a decrease in the intracellular content of glutathione (GSH). Moreover, the treatment with a GSH depleting agent, buthionine sulfoximine (BSO), recapitulates the effect of cold exposure resulting in the induction of thermogenic program. In particular, BSO treatment leads to enhanced uncoupling respiration as demonstrated by increased expression of thermogenic genes (e.g. Ucp1, Ppargc1a), augmented oxygen consumption and decreased mitochondrial transmembrane potential. Buffering GSH decrement by pre-treatment with GSH ester prevents the up-regulation of typical markers of uncoupling respiration. We demonstrate that FoxO1 activation is responsible for the conversion of white adipocytes into a brown phenotype as the “browning” effects of BSO are completely abrogated in cells down-regulating FoxO1. In mice, the BSO-mediated up-regulation of uncoupling genes results in weight loss that is at least in part ascribed to adipose tissue mass reduction. The induction of thermogenic program has been largely proposed to counteract obesity-related diseases. Based on these findings, we propose GSH as a novel therapeutic target to increase energy expenditure in adipocytes.

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

“…In summary, we attempted to extend current data on the obesity-resistance conferred by GSH depletion [13, 14] by characterizing the metabolomic profile of BSO-treated mice. Inhibition of GSH synthesis had widespread effects on the amino acid and fatty acid metabolomes, and on protein and fat metabolism.…”

“…These are mice in which glutamate cysteine ligase (GCL), the rate-limiting GSH synthesis enzyme, is inhibited by a genetic defect (GCL-modifier subunit knockout, Gclm -/- ) [11, 12] or by buthionine sulfoximine (BSO) [13, 14]. Gclm -/- mice also exhibit protection against fatty liver, and hepatic suppression of the lipogenic enzyme stearoyl CoA desaturase-1 (SCD1) [11, 12], but these features have not been tested in BSO-treated mice.…”

Dietary fat overload reprograms brown fat mitochondria

“…Notably, brown adipose tissue (BAT) is involved in glucose clearance in the body thus suggesting that its dysfunction during stage of life could participate in age-related metabolic diseases. As consequence, BAT has currently gathered increasing attention as a therapeutic target for overwhelming human obesity and related metabolic disorders (Tseng et al, 2010 ; Lettieri Barbato et al, 2015 ).…”

Proteomic profiling of Ganoderma tsugae ethanol extract‐induced adipogenesis displaying browning features

“…The browning process was considered an adaptive mechanism to alleviate redox pressure. Furthermore, accumulating evidence have suggested that the induction of the molecular events that orchestrate adipocyte differentiation, metabolism, and even the efficiency of mitochondrial metabolism are driven by changes in the intracellular redox state, such as physiological NADPH oxidase‐induced reactive oxygen species (ROS) and glutathione (GSH) redox state . In addition, a previous study reported that adipocyte differentiation may be enhanced under conditions promoting intracellular and mitochondrial compartment oxidation .…”