Journal
ENDOCRINOLOGY
Volume 150, Issue 3, Pages 1225-1234Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/en.2008-0646
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan.
- Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation and Human Science of Japan [KHC1204]
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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 alpha expression was elevated in the fed state, whereas the fasting-induced up-regulation of PPAR alpha was attenuated. We also detected an increased expression of PPAR gamma coactivator-1 alpha protein in fed TBP-2(-/-) mice. TBP-2 overexpression significantly inhibited PPAR alpha-mediated transcriptional activity induced by a specific PPAR alpha ligand in vitro. These results suggest that TBP-2 is a key regulator of PPAR alpha expression and signaling, and coordinated regulation of PPAR alpha and insulin secretion by TBP-2 is crucial in the feeding-fasting nutritional transition. (Endocrinology 150: 1225-1234, 2009)
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