Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme

Johns Hopkins University, Baltimore, Maryland, United States
Cell Metabolism (Impact Factor: 17.57). 12/2007; 6(5):363-75. DOI: 10.1016/j.cmet.2007.09.003
Source: PubMed


Intracellular nicotinamide phosphoribosyltransferase (iNampt) is an essential enzyme in the NAD biosynthetic pathway. An extracellular form of this protein (eNampt) has been reported to act as a cytokine named PBEF or an insulin-mimetic hormone named visfatin, but its physiological relevance remains controversial. Here we show that eNampt does not exert insulin-mimetic effects in vitro or in vivo but rather exhibits robust NAD biosynthetic activity. Haplodeficiency and chemical inhibition of Nampt cause defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets in vivo and in vitro. These defects are corrected by administration of nicotinamide mononucleotide (NMN), a product of the Nampt reaction. A high concentration of NMN is present in mouse plasma, and plasma eNampt and NMN levels are reduced in Nampt heterozygous females. Our results demonstrate that Nampt-mediated systemic NAD biosynthesis is critical for beta cell function, suggesting a vital framework for the regulation of glucose homeostasis.

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Available from: Biplab Dasgupta, Feb 04, 2014
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    • "For example, exposing adipocytes to glucose in vitro leads to the secretion of visfatin; likewise, in humans, the secretion of visfatin by adipocytes is influenced by glucose blood level (Haider et al., 2006a,b) and it is thus not surprising that obesity is also associated with increased circulating visfatin concentration (Filippatos et al., 2007; Haider et al., 2006a,b; Zahorska-Markiewicz et al., 2007). Very importantly, visfatin modulates glucose homeostasis by regulating insulin secretion in cells as a systemic NAD biosynthetic enzyme (Revollo et al., 2007). Revollo et al. propose that Nampt-mediated systemic NAD biosynthesis might be critical for cell function, suggesting a vital framework for the regulation of glucose homeostasis, which is in line with observed links between visfatin and gestational diabetes, discussed later in this manuscript. "
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    ABSTRACT: Visfatin (PBEF/Nampt) is an adipocytokine that exerts pleiotropic effects within the human body, particularly affecting its metabolism and immunity. Visfatin was originally identified as being secreted by peripheral blood lymphocytes acting as a pre-B-cell colony-enhancing factor (PBEF). However, it was subsequently reported to be expressed in almost every tissue of the human body, with visceral fat deposits being the main source of visfatin. In addition to its secreted form, visfatin may also be found intracellularly where it functions as a nicotinamide phosphoribosyltransferase (Nampt). Visfatin maternal plasma concentrations increase during pregnancy, suggesting its important role in this complicated process. Alterations in visfatin level also take place in patients during pregnancy complications. This review focuses on the ones that most commonly occur in connection with visfatin: preterm labor, pre-eclampsia and gestational diabetes mellitus. The review aims to provide a better understanding of the role of visfatin during pregnancy and the causes of its alteration in maternal plasma, highlighting the potential use of visfatin as a diagnostic marker of pregnancy complications in the future.
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    • "In fact, NAM is an end product of NAD + -consuming activities in the cell (i.e., sirtuins, poly(ADP-ribose) polymerases and cyclic ADP-ribose hydrolases ) (Houtkooper et al., 2010a). Accordingly, mice lacking NAMPT are not viable (Revollo et al., 2007). This, however, does not rule out a limited contribution of circulating NR, NMN, NAM, or Trp to NAD + biosynthesis under basal conditions . "
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    ABSTRACT: With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic NAD+ levels driving reductions in hepatic mitochondrial content, function and ATP levels, in conjunction with robust increases in hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide riboside (NR), a precursor for NAD+ biosynthesis, was given to mice concomitant, as preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and SIRT3-dependent mitochondrial unfolded protein response (UPRmt), triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 KO mice (Sirt1hep-/-), while Apolipoprotein E-deficient (Apoe-/-) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the future evaluation of NAD+ boosting strategies to manage the development or progression of NAFLD. This article is protected by copyright. All rights reserved.
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    • "If active release is responsible for the presence of eNAMPT in the extracellular medium, it should be possible to pharmacologically modulate the amount released. It has been previously suggested that eNAMPT, in hepatocytes and adipocytes, proceeds via a nonclassical (unconventional) release pathway, insensitive to both brefeldin A and monensin (Garten et al., 2010; Revollo et al., 2007; Tanaka et al., 2007). We therefore tested whether monensin or brefeldin might affect the quantity of eNAMPT by incubating cells for 4 hours in MeWo and B16 cells, and comparing the effects to those of "
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    ABSTRACT: High plasma levels of nicotinamide phosphoribosyltransferase (NAMPT), traditionally considered an intracellular enzyme with a key role in NAD synthesis, have been reported in several oncological, inflammatory and metabolic diseases. We now show that eNAMPT can be actively released by melanoma cells in vitro. We analysed the mechanisms of its release and we found both classical and non-classical pathway involvement. eNAMPT released by melanoma cells, in our hands, has paracrine and autocrine effects: it activates MAPK, AKT, NF-κB pathways and increases colony-formation in anchorage-independent conditions. eNAMPT also induces M1 polarization in human monocytes. Last, we demonstrate, for the first time in any cancer type, that eNAMPT levels in plasma of tumour-bearing mice increase and that this increase can be re-conducted to the tumour itself. This provides an important cue on previous observations that eNAMPT is increased in cancer patients. Moreover, silencing NAMPT in melanoma cells leads to a reduction of the tumour growth rate. Our findings extend the basis to consider eNAMPT as a cytokine involved in tumour progression. This article is protected by copyright. All rights reserved.
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