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

Department of Biological Responses (S.O, E.Y., A.B.-A., W.L., M.W., J.Y., H.M.), Institute for Virus Research, and Division of Systemic Life Science (E.Y), Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan

Address all correspondence and requests for reprints to: Hiroshi Masutani, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan. E-mail: hmasutan{at}virus.kyoto-u.ac.jp.

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, PPAR expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPAR was attenuated. We also detected an increased expression of PPAR coactivator-1 protein in fed TBP-2^–/– mice. TBP-2 overexpression significantly inhibited PPAR-mediated transcriptional activity induced by a specific PPAR ligand in vitro. These results suggest that TBP-2 is a key regulator of PPAR expression and signaling, and coordinated regulation of PPAR and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition.

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