Thioredoxin Binding Protein-2/Thioredoxin-Interacting Protein Is a Critical Regulator of Insulin Secretion and Peroxisome Proliferator-Activated Receptor Function

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 proliferator activated receptor (PPAR) target genes, such as CD36, FABP2, ACOT1, and FGF21, to regulate fatty acid consumption. In TBP-2(-/-) mice, PPARalpha expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPARalpha was attenuated. We also detected an increased expression of PPARgamma coactivator-1alpha protein in fed TBP-2(-/-) mice. TBP-2 overexpression significantly inhibited PPARalpha-mediated transcriptional activity induced by a specific PPARalpha ligand in vitro. These results suggest that TBP-2 is a key regulator of PPARalpha expression and signaling, and coordinated regulation of PPARalpha and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition.