Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function

Abstract

The feeding-fasting nutritional transition triggers a dynamic change in metabolic pathways and is a model for understanding how these pathways are mutually organized. The targeted disruption of the thioredoxin binding protein-2 (TBP-2)/thioredoxin-interacting protein (Txnip)/VDUP1 gene in mice results in lethality with hypertriglyceridemia and hypoglycemia during fasting. To investigate the molecular mechanism of the nutritional transition and the role of TBP-2, microarray analyses were performed using the liver of TBP-2 -/- mice in the fed and fasted states. We found that the fasting-induced reduction in the expression of lipogenic genes targeted by insulin (SREBP-1), such as FASN and THRSP, was abolished in TBP-2 -/- mice, and the expression of lipoprotein lipase is down-regulated, which was consistent with the lipoprotein profile. TBP-2 -/- mice also exhibited enhanced glucose-induced insulin secretion and sensitivity. Another feature of the hepatic gene expression in fed TBP-2 -/- mice was the augmented expression of peroxisome prolif-erator activated receptor (PPAR) target genes, such as CD36, FABP2, ACOT1, and FGF21, to regulate fatty acid consumption. In TBP-2 -/-~ mice, PPARα expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPARα was attenuated. We also detected an increased expression of PPARγ coactivator-1β protein in fed TBP-2 -/- mice. TBP-2 overexpression significantly inhibited PPARα-mediated transcriptional activity induced by a specific PPARα ligand in vitro. These results suggest that TBP-2 is a key regulator of PPARα expression and signaling, and coordinated regulation of PPARα and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition. Copyright © 2009 by The Endocrine Society.