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  • Review Article
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Physiological and pathophysiological roles of NAMPT and NAD metabolism

Key Points

  • Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool and, thus, regulates the activity of NAD-dependent enzymes

  • NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance

  • Levels of extracellular NAMPT are associated with various metabolic disorders

  • NAMPT, which has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.

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Figure 1: Mammalian NAD metabolism.
Figure 2: Physiological actions of NAMPT.

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References

  1. Samal, B. et al. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol. Cell. Biol. 14, 1431–1437 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Martin, P. R., Shea, R. J. & Mulks, M. H. Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence. J. Bacteriol. 183, 1168–1174 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rongvaux, A. et al. Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur. J. Immunol. 32, 3225–3234 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Preiss, J. & Handler, P. Enzymatic synthesis of nicotinamide mononucleotide. J. Biol. Chem. 225, 759–770 (1957).

    CAS  PubMed  Google Scholar 

  5. Fukuhara, A. et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426–430 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Chang, Y.-H., Chang, D.-M., Lin, K.-C., Shin, S.-J. & Lee, Y.-J. Visfatin in overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases: a meta-analysis and systemic review. Diabetes Metab. Res. Rev. 27, 515–527 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Garten, A., Petzold, S., Körner, A., Imai, S. & Kiess, W. Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol. Metab. 20, 130–138 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Mori, V. et al. Metabolic profiling of alternative NAD biosynthetic routes in mouse tissues. PLoS ONE 9, e113939 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang, S. J. et al. Nicotinamide improves glucose metabolism and affects the hepatic NAD–sirtuin pathway in a rodent model of obesity and type 2 diabetes. J. Nutr. Biochem. 25, 66–72 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Collins, P. B. & Chaykin, S. The management of nicotinamide and nicotinic acid in the mouse. J. Biol. Chem. 247, 778–783 (1972).

    CAS  PubMed  Google Scholar 

  11. Ushiro, H., Yokoyama, Y. & Shizuta, Y. Purification and characterization of poly(ADP-ribose) synthetase from human placenta. J. Biol. Chem. 262, 2352–2357 (1987).

    CAS  PubMed  Google Scholar 

  12. Guan, X., Lin, P., Knoll, E. & Chakrabarti, R. Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS ONE 9, e107729 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Revollo, J. R., Grimm, A. A. & Imai, S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754–50763 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Bieganowski, P. & Brenner, C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss–Handler independent route to NAD+ in fungi and humans. Cell 117, 495–502 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Nikiforov, A., Dölle, C., Niere, M. & Ziegler, M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J. Biol. Chem. 286, 21767–21778 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Garavaglia, S. et al. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem. J. 441, 131–141 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Grozio, A. et al. CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells. J. Biol. Chem. 288, 25938–25949 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Friebe, D. et al. Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans. Diabetologia 54, 1200–1211 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kitani, T., Okuno, S. & Fujisawa, H. Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor. FEBS Lett. 544, 74–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Revollo, J. R. et al. Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363–375 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang, H. et al. Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pittelli, M. et al. Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J. Biol. Chem. 285, 34106–34114 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Burgos, E. S. & Schramm, V. L. Weak coupling of ATP hydrolysis to the chemical equilibrium of human nicotinamide phosphoribosyltransferase. Biochemistry 47, 11086–11096 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Kim, M.-K. et al. Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866. J. Mol. Biol. 362, 66–77 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, T. et al. Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat. Struct. Mol. Biol. 13, 661–662 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Kang, G. B. et al. Crystal structure of Rattus norvegicus visfatin/PBEF/Nampt in complex with an FK866-based inhibitor. Mol. Cells 27, 667–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Burgos, E. S., Vetticatt, M. J. & Schramm, V. L. Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase. J. Am. Chem. Soc. 135, 3485–3493 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Khan, J. A., Tao, X. & Tong, L. Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents. Nat. Struct. Mol. Biol. 13, 582–588 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Takahashi, R., Nakamura, S., Yoshida, T., Kobayashi, Y. & Ohkubo, T. Crystallization of human nicotinamide phosphoribosyltransferase. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 63, 375–377 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Christensen, M. K. et al. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation, and structure–activity relationship. J. Med. Chem. 56, 9071–9088 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Hasmann, M. & Schemainda, I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res. 63, 7436–7442 (2003).

    CAS  PubMed  Google Scholar 

  33. Bowlby, S. C., Thomas, M. J., D'Agostino, R. B. & Kridel, S. J. Nicotinamide phosphoribosyl transferase (Nampt) is required for de novo lipogenesis in tumor cells. PLoS ONE 7, e40195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bruzzone, S. et al. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS ONE 4, e7897 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koltai, E. et al. Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech. Ageing Dev. 131, 21–28 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Van Gool, F. et al. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nat. Med. 15, 206–210 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pillai, J. B., Isbatan, A., Imai, S. & Gupta, M. P. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2α deacetylase activity. J. Biol. Chem. 280, 43121–43130 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Rodgers, J. T., Lerin, C., Gerhart-Hines, Z. & Puigserver, P. Metabolic adaptations through the PGC-1 α and SIRT1 pathways. FEBS Lett. 582, 46–53 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Van der Horst, A. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2 (SIRT1). J. Biol. Chem. 279, 28873–28879 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Bordone, L. et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS Biol. 4, e31 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Luo, X. & Kraus, W. L. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 26, 417–432 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mouchiroud, L., Houtkooper, R. H. & Auwerx, J. NAD+ metabolism: a therapeutic target for age-related metabolic disease. Crit. Rev. Biochem. Mol. Biol. 48, 397–408 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Dölle, C., Skoge, R. H., Vanlinden, M. R. & Ziegler, M. NAD biosynthesis in humans—enzymes, metabolites and therapeutic aspects. Curr. Top. Med. Chem. 13, 2907–2917 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Chang, H.-C. & Guarente, L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab. 25, 138–145 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Imai, S. & Kiess, W. Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Front. Biosci. (Landmark Ed.) 14, 2983–2995 (2009).

    Article  CAS  Google Scholar 

  46. Bürkle, A. & Virág, L. Poly(ADP-ribose): PARadigms and PARadoxes. Mol. Aspects Med. 34, 1046–1065 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Scarpa, E. S., Fabrizio, G. & Di Girolamo, M. A role of intracellular mono-ADP-ribosylation in cancer biology. FEBS J. 280, 3551–3562 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Lee, H. C. & Aarhus, R. ADP-ribosyl cyclase: an enzyme that cyclizes NAD+ into a calcium-mobilizing metabolite. Cell Regul. 2, 203–209 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324, 651–654 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCK–SIRT1. Science 324, 654–657 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Korner, A. et al. Molecular characteristics of serum visfatin and differential detection by immunoassays. J. Clin. Endocrinol. Metab. 92, 4783–4791 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Hallschmid, M., Randeva, H., Tan, B. K., Kern, W. & Lehnert, H. Relationship between cerebrospinal fluid visfatin (PBEF/Nampt) levels and adiposity in humans. Diabetes 58, 637–640 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Thomas, S. et al. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil. Steril. 99, 1256–1263 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Tanaka, M. et al. Visfatin is released from 3T3-L1 adipocytes via a non-classical pathway. Biochem. Biophys. Res. Commun. 359, 194–201 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Yoon, M. J. et al. SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice. Cell. Metab. 21, 706–717 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Garten, A. et al. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem. Biophys. Res. Commun. 391, 376–381 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Schuster, S. et al. Resveratrol differentially regulates NAMPT and SIRT1 in hepatocarcinoma cells and primary human hepatocytes. PLoS ONE 9, e91045 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pillai, V. B. et al. Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling. Am. J. Physiol. Heart Circ. Physiol. 304, H415–H426 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Zhao, B. et al. Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non-enzymatic mechanism. PLoS ONE 8, e85403 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jing, Z. et al. Neuronal NAMPT is released after cerebral ischemia and protects against white matter injury. J. Cereb. Blood Flow Metab. 34, 1613–1621 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ognjanovic, S. & Bryant-Greenwood, G. D. Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes. Am. J. Obstet. Gynecol. 187, 1051–1058 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Kover, K. et al. Expression and regulation of nampt in human islets. PLoS ONE 8, e58767 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Schilling, E. & Hauschildt, S. Extracellular ATP induces P2X7-dependent nicotinamide phosphoribosyltransferase release in LPS-activated human monocytes. Innate Immun. 18, 738–744 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Van den Bergh, R. et al. Monocytes contribute to differential immune pressure on R5 versus X4 HIV through the adipocytokine visfatin/NAMPT. PLoS ONE 7, e35074 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Choi, Y. J. et al. Extracellular visfatin activates gluconeogenesis in HepG2 cells through the classical PKA/CREB-dependent pathway. Horm. Metab. Res. 46, 233–239 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Kim, S.-R. et al. Visfatin promotes angiogenesis by activation of extracellular signal-regulated kinase 1/2. Biochem. Biophys. Res. Commun. 357, 150–156 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Bae, Y.-H. et al. Upregulation of fibroblast growth factor-2 by visfatin that promotes endothelial angiogenesis. Biochem. Biophys. Res. Commun. 379, 206–211 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Kang, Y.-S. et al. Visfatin induces neurite outgrowth in PC12 cells via ERK1/2 signaling pathway. Neurosci. Lett. 504, 121–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Park, H.-J. et al. Visfatin promotes cell and tumor growth by upregulating Notch1 in breast cancer. Oncotarget 5, 5087–5099 (2014).

    PubMed  PubMed Central  Google Scholar 

  70. Zamporlini, F. et al. Novel assay for simultaneous measurement of pyridine mononucleotides synthesizing activities allows dissection of NAD+ biosynthetic machinery in mammalian cells. FEBS J. 281, 5104–5119 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Formentini, L., Moroni, F. & Chiarugi, A. Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo. Biochem. Pharmacol. 77, 1612–1620 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Hara, N., Yamada, K., Shibata, T., Osago, H. & Tsuchiya, M. Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS ONE 6, e22781 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Khan, M. & Joseph, F. Adipose tissue and adipokines: the association with and application of adipokines in obesity. Scientifica (Cairo) 2014, 328592 (2014).

    Google Scholar 

  74. Olarescu, N. C. et al. Adipocytes as a source of increased circulating levels of nicotinamide phosphoribosyltransferase/visfatin in active acromegaly. J. Clin. Endocrinol. Metab. 97, 1355–1362 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Blakemore, A. I. et al. A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity. Obesity (Silver Spring) 17, 1549–1553 (2009).

    Article  CAS  Google Scholar 

  76. Saddi-Rosa, P. et al. Association of circulating levels of nicotinamide phosphoribosyltransferase (NAMPT/Visfatin) and of a frequent polymorphism in the promoter of the NAMPT gene with coronary artery disease in diabetic and non-diabetic subjects. Cardiovasc. Diabetol. 12, 119 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jian, W.-X. et al. The visfatin gene is associated with glucose and lipid metabolism in a Chinese population. Diabet. Med. 23, 967–973 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Paschou, P. et al. Genetic variation in the visfatin (PBEF1/NAMPT) gene and type 2 diabetes in the Greek population. Cytokine 51, 25–27 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Körner, A. et al. Effects of genetic variation in the visfatin gene (PBEF1) on obesity, glucose metabolism, and blood pressure in children. Metabolism. 56, 772–777 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Böttcher, Y. et al. Genetic variation in the visfatin gene (PBEF1) and its relation to glucose metabolism and fat-depot-specific messenger ribonucleic acid expression in humans. J. Clin. Endocrinol. Metab. 91, 2725–2731 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Haider, D. G. et al. The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia 49, 1909–1914 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Haider, D. G. et al. Increased plasma visfatin concentrations in morbidly obese subjects are reduced after gastric banding. J. Clin. Endocrinol. Metab. 91, 1578–1581 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, Y., Chen, M., Wu, Z. & Zhao, S. Ox-LDL induces ER stress and promotes the adipokines secretion in 3T3-L1 adipocytes. PLoS ONE 8, e81379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kralisch, S. et al. Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes. J. Endocrinol. 185, R1–R8 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Kralisch, S. et al. Interleukin-6 is a negative regulator of visfatin gene expression in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 289, E586–E590 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Friebe, D. et al. Impact of metabolic regulators on the expression of the obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. PLoS ONE 6, e19526 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kim, H.-S. et al. Blockade of visfatin induction by oleanolic acid via disturbing IL-6-TRAF6-NF-κB signaling of adipocytes. Exp. Biol. Med. (Maywood) 239, 284–292 (2014).

    Article  CAS  Google Scholar 

  88. Segawa, K. et al. Visfatin in adipocytes is upregulated by hypoxia through HIF1α-dependent mechanism. Biochem. Biophys. Res. Commun. 349, 875–882 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Curat, C. A. et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49, 744–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Romacho, T., Sánchez-Ferrer, C. F. & Peiró, C. Visfatin/Nampt: an adipokine with cardiovascular impact. Mediators Inflamm. 2013, 946427 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li, Y. et al. Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6/STAT3 signaling mechanism. J. Biol. Chem. 283, 34833–34843 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Romacho, T. et al. Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory signalling in human vascular smooth muscle cells through nicotinamide phosphoribosyltransferase activity. Diabetologia 52, 2455–2463 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Moschen, A. R., Gerner, R. R. & Tilg, H. Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders. Curr. Pharm. Des. 16, 1913–1920 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Hector, J. et al. TNF-α alters visfatin and adiponectin levels in human fat. Horm. Metab. Res. 39, 250–255 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Song, H. K. et al. Visfatin: a new player in mesangial cell physiology and diabetic nephropathy. Am. J. Physiol. Renal Physiol. 295, F1485–F1494 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Sommer, G. et al. Visfatin is a positive regulator of MCP-1 in human adipocytes in vitro and in mice in vivo. Obesity (Silver Spring) 18, 1486–1492 (2010).

    Article  CAS  Google Scholar 

  97. Yang, C. C. et al. Visfatin regulates genes related to lipid metabolism in porcine adipocytes. J. Anim. Sci. 88, 3233–3241 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Salgado-Delgado, R. C. et al. Shift work or food intake during the rest phase promotes metabolic disruption and desynchrony of liver genes in male rats. PLoS ONE 8, e60052 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Barclay, J. L. et al. Circadian desynchrony promotes metabolic disruption in a mouse model of shiftwork. PLoS ONE 7, e37150 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Karlsson, B., Knutsson, A. & Lindahl, B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup. Environ. Med. 58, 747–752 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Benedict, C. et al. Diurnal rhythm of circulating nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF): impact of sleep loss and relation to glucose metabolism. J. Clin. Endocrinol. Metab. 97, E218–E222 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Cline, M. A., Nandar, W., Prall, B. C., Bowden, C. N. & Denbow, D. M. Central visfatin causes orexigenic effects in chicks. Behav. Brain Res. 186, 293–297 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Brunetti, L. et al. Effects of visfatin/PBEF/NAMPT on feeding behaviour and hypothalamic neuromodulators in the rat. J. Biol. Regul. Homeost. Agents 26, 295–302 (2012).

    CAS  PubMed  Google Scholar 

  104. Cantó, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  106. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  107. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  108. Tarantino, G. & Finelli, C. What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? World J. Gastroenterol. 19, 3375–3384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Aller, R. et al. Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease. Dig. Dis. Sci. 54, 1772–1777 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Auguet, T. et al. Plasma visfatin levels and gene expression in morbidly obese women with associated fatty liver disease. Clin. Biochem. 46, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Genc, H. et al. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann. Hepatol. 12, 548–555 (2013).

    Article  PubMed  Google Scholar 

  112. Akbal, E., Kocak, E., Tas, A., Yuksel, E. & Koklu, S. Visfatin levels in nonalcoholic fatty liver disease. J. Clin. Lab. Anal. 26, 115–119 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dahl, T. B. et al. Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 95, 3039–3047 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Gaddipati, R. et al. Visceral adipose tissue visfatin in nonalcoholic fatty liver disease. Ann. Hepatol. 9, 266–270 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Kukla, M. M. et al. Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery. Polish J. Pathol. 61, 147–153 (2010).

    Google Scholar 

  116. Zhang, Z.-F. et al. Troxerutin improves hepatic lipid homeostasis by restoring NAD+-depletion-mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice. Biochem. Pharmacol. 91, 74–86 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Li, H., Xu, M., Lee, J., He, C. & Xie, Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am. J. Physiol. Endocrinol. Metab. 303, E1234–E1244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tao, R. et al. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J. Biol. Chem. 286, 14681–14690 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Castro, R. E. et al. miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease. J. Hepatol. 58, 119–125 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Choi, S.-E. et al. Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT. Aging Cell 12, 1062–1072 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Frederick, D. W. et al. Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism. J. Biol. Chem. 290, 1546–1558 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Escande, C. et al. Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. J. Clin. Invest. 120, 545–558 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Choi, Y. J. et al. Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes. Metabolism 60, 1781–1789 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Al-Goblan, A. S., Al-Alfi, M. A. & Khan, M. Z. Mechanism linking diabetes mellitus and obesity. Diabetes. Metab. Syndr. Obes. 7, 587–591 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Gulcelik, N. E., Usman, A. & Gürlek, A. Role of adipocytokines in predicting the development of diabetes and its late complications. Endocrine 36, 397–403 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Blüher, M. Adipokines—removing road blocks to obesity and diabetes therapy. Mol. Metab. 3, 230–240 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hug, C. & Lodish, H. F. Medicine. Visfatin: a new adipokine. Science 307, 366–367 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Varma, V. et al. Human visfatin expression: relationship to insulin sensitivity, intramyocellular lipids, and inflammation. J. Clin. Endocrinol. Metab. 92, 666–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Hajianfar, H., Bahonar, A., Entezari, M. H., Askari, G. & Yazdani, M. Lipid profiles and serum visfatin concentrations in patients with type II diabetes in comparison with healthy controls. Int. J. Prev. Med. 3, 326–331 (2012).

    PubMed  PubMed Central  Google Scholar 

  131. El-Mesallamy, H. O., Kassem, D. H., El-Demerdash, E. & Amin, A. I. Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus. Metabolism 60, 63–70 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Chen, M.-P. et al. Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 91, 295–299 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. López-Bermejo, A. et al. Serum visfatin increases with progressive β-cell deterioration. Diabetes 55, 2871–2875 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Yilmaz, M. I. et al. Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin. Nephrol. Dial. Transplant. 23, 1621–1627 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Motawi, T. M., Shaker, O. G., El-Sawalhi, M. M. & Abdel-Nasser, Z. M. Visfatin −948G/T and resistin −420C/G. polymorphisms in Egyptian type 2 diabetic patients with and without cardiovascular diseases. Genome 57, 259–266 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Xie, H. et al. Insulin-like effects of visfatin on human osteoblasts. Calcif. Tissue Int. 80, 201–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Ramsey, K. M., Mills, K. F., Satoh, A. & Imai, S.-I. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in β cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell 7, 78–88 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Spinnler, R. et al. The adipocytokine Nampt and its product NMN have no effect on β-cell survival but potentiate glucose stimulated insulin secretion. PLoS ONE 8, e54106 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yoshino, J., Mills, K. F., Yoon, M. J. & Imai, S. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Caton, P. W., Kieswich, J., Yaqoob, M. M., Holness, M. J. & Sugden, M. C. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia 54, 3083–3092 (2011).

    Article  CAS  PubMed  Google Scholar 

  141. Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Van der Veer, E. et al. Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282, 10841–10845 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Villalobos, L. A. et al. Visfatin/Nampt induces telomere damage and senescence in human endothelial cells. Int. J. Cardiol. 175, 573–575 (2014).

    Article  PubMed  Google Scholar 

  144. Song, J. et al. Nicotinamide phosphoribosyltransferase is required for the calorie restriction-mediated improvements in oxidative stress, mitochondrial biogenesis, and metabolic adaptation. J. Gerontol. A Biol. Sci. Med. Sci. 69, 44–57 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. Artegiani, B. & Calegari, F. Age-related cognitive decline: can neural stem cells help us? Aging (Albany NY) 4, 176–186 (2012).

    Article  Google Scholar 

  146. Stein, L. R. & Imai, S. I. Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging. EMBO J. 33, 1321–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Olszanecka-Glinianowicz, M. et al. Relationship between circulating visfatin/NAMPT, nutritional status and insulin resistance in an elderly population—results from the PolSenior substudy. Metabolism 63, 1409–1418 (2014).

    Article  CAS  PubMed  Google Scholar 

  148. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Cavadini, G. et al. TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc. Natl Acad. Sci. USA 104, 12843–12848 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956).

    CAS  PubMed  Google Scholar 

  151. Chiarugi, A., Dölle, C., Felici, R. & Ziegler, M. The NAD metabolome—a key determinant of cancer cell biology. Nat. Rev. Cancer 12, 741–752 (2012).

    Article  CAS  PubMed  Google Scholar 

  152. Schuster, S. et al. FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signalling in hepatocarcinoma cells. Biochem. Biophys. Res. Commun. 458, 334–340 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Nahimana, A. et al. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. Blood 113, 3276–3286 (2009).

    Article  CAS  PubMed  Google Scholar 

  154. Olesen, U. H. et al. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem. Biophys. Res. Commun. 367, 799–804 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Galli, U. et al. Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. J. Med. Chem. 56, 6279–6296 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Zhou, T., Wang, T. & Garcia, J. G. Expression of nicotinamide phosphoribosyltransferase-influenced genes predicts recurrence-free survival in lung and breast cancers. Sci. Rep. 4, 6107 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Cea, M. et al. Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition. Blood 120, 3519–3529 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Thakur, B. K. et al. Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells. Int. J. Cancer 132, 766–774 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Zhang, K. et al. Genetic variants in NAMPT predict bladder cancer risk and prognosis in individuals from southwest Chinese Han group. Tumour Biol. 35, 4031–4040 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Tian, W. et al. Visfatin, a potential biomarker and prognostic factor for endometrial cancer. Gynecol. Oncol. 129, 505–512 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Reddy, P. S. et al. PBEF1/NAmPRTase/Visfatin: a potential malignant astrocytoma/glioblastoma serum marker with prognostic value. Cancer Biol. Ther. 7, 663–668 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Ninomiya, S. et al. Possible role of visfatin in hepatoma progression and the effects of branched-chain amino acids on visfatin-induced proliferation in human hepatoma cells. Cancer Prev. Res. (Phila.) 4, 2092–2100 (2011).

    Article  CAS  Google Scholar 

  163. Audrito, V. et al. Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia. Blood 125, 111–123 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Bułdak, R. J. et al. Visfatin affects redox adaptative responses and proliferation in Me45 human malignant melanoma cells: an in vitro study. Oncol. Rep. 29, 771–778 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Adya, R., Tan, B. K., Punn, A., Chen, J. & Randeva, H. S. Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc. Res. 78, 356–365 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Olesen, U. H. et al. Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase. BMC Cancer 10, 677 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bi, T.-Q. et al. Overexpression of Nampt in gastric cancer and chemopotentiating effects of the Nampt inhibitor FK866 in combination with fluorouracil. Oncol. Rep. 26, 1251–1257 (2011).

    CAS  PubMed  Google Scholar 

  168. Gehrke, I. et al. On-target effect of FK866, a nicotinamide phosphoribosyl transferase inhibitor, by apoptosis-mediated death in chronic lymphocytic leukemia cells. Clin. Cancer Res. 20, 4861–4872 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Cea, M. et al. APO866 activity in hematologic malignancies: a preclinical in vitro study. Blood 113, 6035–6037 (2009).

    Article  CAS  PubMed  Google Scholar 

  170. Soncini, D. et al. Nicotinamide phosphoribosyltransferase promotes epithelial-to-mesenchymal transition as a soluble factor independent of its enzymatic activity. J. Biol. Chem. 289, 34189–34204 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Tan, B. et al. Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD+ biosynthesis, in human cancer cells: metabolic basis and potential clinical implications. J. Biol. Chem. 288, 3500–3511 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Tummala, K. S. et al. Inhibition of de novo NAD+ synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell 26, 826–839 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Von Heideman, A., Berglund, A., Larsson, R. & Nygren, P. Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother. Pharmacol. 65, 1165–1172 (2010).

    Article  CAS  PubMed  Google Scholar 

  174. Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A.-R. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs 26, 45–51 (2008).

    Article  CAS  PubMed  Google Scholar 

  175. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  176. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  177. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  178. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  179. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  180. US National Library of Medicine. ClinicalTrials.gov[online], (2015).

  181. Chan, M. et al. Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption. Cancer Res. 74, 5948–5954 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Hosseinzadeh-Attar, M. J., Golpaie, A., Janani, L. & Derakhshanian, H. Effect of weight reduction following bariatric surgery on serum visfatin and adiponectin levels in morbidly obese subjects. Obes. Facts 6, 193–202 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Saboori, S. et al. The comparison of serum vaspin and visfatin concentrations in obese and normal weight women. Diabetes Metab. Syndr. http://dx.doi.org/10.1016/j.dsx.2013.10.009.

  184. Li, R.-Z. et al. Elevated visfatin levels in obese children are related to proinflammatory factors. J. Pediatr. Endocrinol. Metab. 26, 111–118 (2013).

    PubMed  Google Scholar 

  185. Jaleel, A. et al. Association of adipokines with obesity in children and adolescents. Biomark. Med. 7, 731–735 (2013).

    Article  CAS  PubMed  Google Scholar 

  186. Terra, X. et al. Increased levels and adipose tissue expression of visfatin in morbidly obese women: the relationship with pro-inflammatory cytokines. Clin. Endocrinol. (Oxf.) 77, 691–698 (2012).

    Article  CAS  Google Scholar 

  187. Taskesen, D., Kirel, B. & Us, T. Serum visfatin levels, adiposity and glucose metabolism in obese adolescents. J. Clin. Res. Pediatr. Endocrinol. 4, 76–81 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Catalan, V. et al. Association of increased visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity. Nutr. Metab. Cardiovasc. Dis. 21, 245–253 (2011).

    CAS  PubMed  Google Scholar 

  189. Reda, R., Shehab, A., Soliman, D., Gabr, A. & Abbass, A. Serum visfatin levels in a group of Egyptian obese individuals. Egypt. J. Immunol. 18, 25–32 (2011).

    PubMed  Google Scholar 

  190. Krzystek-Korpacka, M., Patryn, E., Bednarz-Misa, I., Hotowy, K. & Noczynska, A. Visfatin in juvenile obesity—the effect of obesity intervention and sex. Eur. J. Clin. Invest. 41, 1284–1291 (2011).

    Article  CAS  PubMed  Google Scholar 

  191. Martos-Moreno, G. Á. et al. Serum visfatin and vaspin levels in prepubertal children: effect of obesity and weight loss after behavior modifications on their secretion and relationship with glucose metabolism. Int. J. Obes. (Lond.) 35, 1355–1362 (2011).

    Article  CAS  Google Scholar 

  192. Ersoy, C. et al. Body fat distribution has no effect on serum visfatin levels in healthy female subjects. Cytokine 49, 275–278 (2010).

    Article  CAS  PubMed  Google Scholar 

  193. Kaminska, A. et al. An evaluation of visfatin levels in obese subjects. Endokrynol. Pol. 61, 169–173 (2010).

    CAS  PubMed  Google Scholar 

  194. Barth, S. et al. Expression of neuropeptide Y, omentin and visfatin in visceral and subcutaneous adipose tissues in humans: relation to endocrine and clinical parameters. Obes. Facts 3, 245–251 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Costford, S. R. et al. Skeletal muscle NAMPT is induced by exercise in humans. Am. J. Physiol. Endocrinol. Metab. 298, E117–E126 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Nowell, M. A. et al. Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 54, 2084–2095 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. Bae, S.-K. et al. Hypoxic induction of human visfatin gene is directly mediated by hypoxia-inducible factor-1. FEBS Lett. 580, 4105–4113 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank colleagues from the Kiess laboratory for valuable discussions and acknowledge support from the German Diabetes Society, the German Competence Network Obesity, the Federal Ministry of Education and Research (grant 01GI1330 to A.G.), the Mitteldeutsche Kinderkrebsstiftung, the University of Chieti, Italy (for a scholarship to T.d.G.) and LIFE (Leipzig Research Centre for Civilization Diseases, University of Leipzig, Germany). LIFE is funded by the European Union, the European Regional Development Fund (ERDF; grant number: 4-7,531.70/5/4) and the Free State of Saxony within the framework of the excellence initiative.

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S.S., M.P., T.G. and T.d.G. researched data for the article. A.G., S.S., M.P., T.G., T.d.G. and W.K. provided substantial contributions to discussions of the content. A.G., S.S., M.P., T.G. and T.d.G. wrote the article. A.G., S.S. and W.K. reviewed and/or edited the manuscript before submission.

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Correspondence to Wieland Kiess.

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Garten, A., Schuster, S., Penke, M. et al. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol 11, 535–546 (2015). https://doi.org/10.1038/nrendo.2015.117

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