Atherobesity - DFG KFO 152 "Fett und Gefäß"

Subproject 7: Characterization of Nicotinamid-Phosphoribosyltransferase (Nampt) as a Link Between NAD-Biosynthesis and Metabolism

Principal Investigators:

 

Dr. rer. nat. Antje Garten Prof. Dr. med. Wieland Kiess
Child and Adolescent Medicine Clinic, Pediatric Research Center Child and Adolescent Medicine Clinic
Universität Leipzig Universität Leipzig
Liebigstraße 21 Liebigstraße 20 a
04103 Leipzig 04103 Leipzig
Phone: +49 341 97 26504 Phone: +49 341 97 26000
Fax: +49 341 97 26069 Fax: +49 341 97 26009
antje.garten@medizin.uni-leipzig.de wieland.kiess@medizin.uni-leipzig.de

 

Summary of the Subproject:

Nampt is a key enzyme of the human NAD biosynthesis originating from nicotinamide. Intracellular Nampt affects the activity of NAD dependent enzymes (e.g. sirtuins), which influence cellular stress responses as well as cell metabolism. Nampt secreted from adipocytes produces nicotinamide mononucleotide (NMN) which causes an increase of insulin secretion in a heterozygous Nampt knock-out mouse model. Based on these results we want to 1) characterize the function of intracellular Nampt in the metabolism of human hepatocytes and 2) investigate the relevance of secreted Nampt in human glucose metabolism. The experiments will be carried out in HepG2 cells and – for verification – in human hepatocytes. 1) By means of an inducible Nampt overexpression model we will analyze the influence of Nampt activity on metabolic end points of the glucose and lipid metabolism. Additionally, we are going to investigate to what extent Nampt expression affects the resistance to cell stress. 2) The enzymatic activity of extracellular Nampt will be quantified by an enzyme assay and NMN and NAD will be measured by HPLC. Subsequently, the biological effects of NMN on glucose metabolism will analyzed in several cell models (measurement of relevant cell responses, e.g. glucose uptake, glucose synthesis).

Publications:

  1. Revollo JR, Körner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007;6:363-75.
  2. Garten A, Petzold S, Körner A, Imai S, Kiess W. Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol Metab. 2009;20:130-8.
  3. Garten A, Petzold S, Barnikol-Oettler A, Körner A, Thasler WE, Kratzsch J, Kiess W, Gebhardt R. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem Biophys Res Commun. 2010;391:376-81.
  4. Vogel R, Garten A, Klammt J, Barnikol-Oettler A, Kiess W. Activation of Erk1/2 phosphorylation but not of Akt/Pkb through an inducible CSF1R/IRR-receptor construct in INS-1E beta-cells. Arch Physiol Biochem. 2010;116:128-36.
  5. Olesen UH, Petersen JG, Garten A, Kiess W, Yoshino J, Imai SI, Christensen MK, Fristrup P, Thougaard AV, Bjorkling F, Jensen PB, Nielsen SJ, Sehested M. Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase. BMC Cancer. 2010;10:677.
  6. Friebe D, Neef M, Kratzsch J, Erbs S, Dittrich K, Garten A, Petzold-Quinque S, Blüher S, Reinehr T, Stumvoll M, Blüher M, Kiess W, Körner A. Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans. Diabetologia. 2011;54:1200-11.
  7. Spinnler R, Gorski T, Stolz K, Schuster S, Garten A, Beck-Sickinger AG, Engelse MA, de Koning EJ, Körner A, Kiess W, Maedler K. The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion. PLoS One. 2013;8:e54106.
Imprint | Contact | © 2014 Author: Prof. Dr. M. Blüher