# Glutathione Decrement Drives Thermogenic Program In Adipose Cells

## TL;DR

Reducing glutathione in fat cells triggers a thermogenic response, potentially offering a new way to combat obesity.

## Contribution

This study identifies glutathione decrement as a driver of thermogenic program activation in adipose cells.

## Key findings

- GSH depletion via BSO mimics cold exposure by inducing thermogenic gene expression and uncoupling respiration.
- GSH ester prevents thermogenic activation, confirming GSH decrement's role in the process.
- FoxO1 activation is essential for the browning of white adipocytes triggered by GSH depletion.

## 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.