title: 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.
authors.affiliation: Dept. Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Lettieri Barbato
authors.affiliation: Scientific Institute for Research Hospitalization and Health Care and Università Telematica San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tatulli
authors.affiliation: Dept. Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Maria Cannata
authors.affiliation: Dept. Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.affiliation: 1] Dept. Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy [2] Scientific Institute for Research Hospitalization and Health Care and Università Telematica San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Aquilano
authors.affiliation: 1] Dept. Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133 Rome, Italy [2] Scientific Institute for Research Hospitalization and Health Care and Università Telematica San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Ciriolo
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology; D000818:Animals; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004822:Epididymis / Q000166:cytology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022722:Thermogenesis
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D005978:Glutathione