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Reduced expression of the INDY (I'm not dead yet) tricarboxylate carrier increased life span in different species by mechanisms akin to caloric restriction. The mammalian INDY homolog (mIndy) gene expression seems to be regulated by hormonal and/or nutritional factors. The underlying mechanisms are still unknown. The current study revealed that mIndy expression and [14C]-citrate uptake was induced by physiological concentrations of glucagon via a cAMP- and cAMP-responsive-element-binding protein (CREB)-dependent mechanism in primary rat hepatocytes. The promoter sequence of mIndy located upstream of the most frequent transcription start site was determined by 5'-race. In silico analysis identified a CREB-binding site within this promoter fragment of mIndy. Functional relevance for the CREB-binding site was demonstrated with reporter gene constructs, which were induced by CREB activation when under the control of a fragment of wild type promoter whereas promoter activity was lost after site directed mutagenesis of the CREB-binding site. Moreover, CREB binding to this promoter element was confirmed by chromatin immunoprecipiation in rat liver. In vivo studies revealed that mIndy was induced in livers of fasted as well as HFD-streptozotocin-diabetic rats, in which CREB is constitutively activated. mIndy induction was completely prevented when CREB was depleted in these rats by antisense oligonucleotides. Together, these data suggest that mIndy is a CREB-dependent glucagon target gene, which is induced in fasting and in type 2 diabetes. Increased mINDY expression might contribute to the metabolic consequences of diabetes in the liver. [ABSTRACT FROM AUTHOR]