The Mammalian INDY Homolog is Induced by CREB in a Rat Model of Type 2 Diabetes

  1. Andreas L. Birkenfeld2
  1. 1University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Potsdam, Germany
  2. 2Charité – University School of Medicine, Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Berlin, Germany
  3. 3German Institute of Human Nutrition Potsdam Rehbrücke, Department of Clinical Nutrition, Nuthetal, Germany
  4. 4Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA
  5. 5Cardiovascular, Metabolic & Endocrine Disease Research Unit, Pfizer, Inc. Cambridge, MA, USA
  6. 6Department of Anesthesiology and Intensive Care, and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
  1. aCorresponding Author: Gerhard P. Püschel, E-mail: gpuesche{at}


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.

  • Received May 8, 2013.
  • Accepted November 5, 2013.

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