Upregulation of the thioredoxin-dependent redox system during differentiation of 3T3-L1 cells to adipocytes

Abstract

Hydrogen peroxide acts as a signaling molecule in early adipogenesis. In differentiating adipocytes, elevated hydrogen peroxide generation is balanced through induction of antioxidant enzymes such as catalase and peroxiredoxins. Thioredoxin reductases (TrxR) and glutathione peroxidases (GPx) are selenoenzymes that constitute part of the major thiol-dependent antioxidant systems in cells. Here we show that the protein levels of cytoplasmic/nuclear TrxR1 and mitochondrial TrxR2 increase in the course of adipocyte differentiation of 3T3-L1 cells together with the TrxR2 substrate thioredoxin 2 (Trx2), resulting in elevated TrxR activity in mature adipocytes. Gene and protein expression of the GPx isoenzyme GPx4 was also stimulated during adipogenesis. Chronic exposure of 3T3-L1 cells to the anti-adipogenic factors tumor necrosis factor α (TNF-α) or rapamycin during differentiation suppressed TrxR1 and Trx2 upregulation, concomitantly with inhibition of adipogenesis and lipogenesis. In contrast, TNF-α or rapamycin did not affect expression of TrxRs and their Trx substrates in mature adipocytes. These results indicate that upregulation of the thioredoxin-dependent redox system is linked to the development of an adipocyte phenotype.

Redox modulation of adipocyte differentiation: hypothesis of “Redox Chain” and novel insights into intervention of adipogenesis and obesity

“…GPx4 is stimulated in the course of 3T3-L1 adipocyte differentiation [252]. GPx7 is highly enriched in WAT [253] and is mainly expressed in preadipocytes but not mature adipocytes of WAT [253].…”

Redox regulation of FoxO transcription factors

“…H 2 O 2 is thought to serve as signaling molecule to increase the stimulating action of insulin on adipogenesis and lipogenesis; exogenous application of H 2 O 2 may both induce and augment adipocyte differentiation of preadipocytes [173,223] . On the other hand, excessive ROS generation would be detrimental and is thus counteracted through staggered induction of antioxidant enzymes such as isoforms of the glutathione peroxidase and thioredoxin reductase selenoenzymes and the FoxO target genes SOD-2 and catalase [173,222,224] . Gene expression and protein synthesis, intracellular localization and posttranslational modifications (phosphorylation, acetylation) of FoxO proteins are tightly and timely regulated in the course of adipocyte differentiation: FoxO1a, FoxO3a and FoxO4 mRNA and protein levels are very low in preadipocytes and increase during adipogenesis, with FoxO1a being the major FoxO isoform in mature adipocytes and in adipose tissue [171,173] .…”

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…Certain studies demonstrated the role of TXNRDs in modulation of adipogenesis [187]. Adipocyte differentiation is associated with increased activity of both Txnrd1 and Txnrd2 along with Gpx4, whereas antiadipogenic agents decreased Txnrd activation in preadipocytes, but not in mature adipocytes [188]. Correspondingly, TXNRDs transcription in human SAT is significantly associated with lipogenesis and insulin resistance in adipocytes [99].…”