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

Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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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    • "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: NAD(+) has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD(+) metabolism revived interest in NAD(+)-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; DOI:10.1016/j.cmet.2015.05.023 · 17.57 Impact Factor
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    • "y that significant extracellular amounts of this nucleotide can arise as a result of cell damage , because the intracellular concentration was measured to be only around 1 mM ( Trammell & Brenner , 2013 ) . However , the possibility exists that NMN could be synthesized in plasma owing to the presence of an extracellular form of NamPRT ( eNAMPT ) ( Revollo et al . , 2007 ) , previously identified as pre - B cell colony enhancing factor ( PBEF ) ( Samal et al . , 1994 ) and also as adipocytokine visfatin ( Fukuhara et al . , 2005 ) . It has been proposed that eNAMPT possesses signaling functions in adipocytes and pancreatic b - cells ( Garten et al . , 2009 ) ."
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    ABSTRACT: The metabolism of NAD has emerged as a key regulator of cellular and organismal homeostasis. Being a major component of both bioenergetic and signaling pathways, the molecule is ideally suited to regulate metabolism and major cellular events. In humans, NAD is synthesized from vitamin B3 precursors, most prominently from nicotinamide, which is the degradation product of all NAD-dependent signaling reactions. The scope of NAD-mediated regulatory processes is wide including enzyme regulation, control of gene expression and health span, DNA repair, cell cycle regulation and calcium signaling. In these processes, nicotinamide is cleaved from NAD(+) and the remaining ADP-ribosyl moiety used to modify proteins (deacetylation by sirtuins or ADP-ribosylation) or to generate calcium-mobilizing agents such as cyclic ADP-ribose. This review will also emphasize the role of the intermediates in the NAD metabolome, their intra- and extra-cellular conversions and potential contributions to subcellular compartmentalization of NAD pools.
    Critical Reviews in Biochemistry and Molecular Biology 04/2015; DOI:10.3109/10409238.2015.1028612 · 7.71 Impact Factor
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    • "The resveratrol treatment partially enhanced visfatin expression in skeletal muscle, but had no effect in pancreas of the diabetic rats (Figure 3A and B). This intracellular and extracellular nicotinamide mononucleotide biosynthetic enzyme has a key role in glucose-stimulated insulin secretion (Revollo et al., 2007), and maintenance of -cell function (Tanaka & Nabeshima, 2007). Lacking resveratrol effect on the visfatin expression on pancreas, but on skeletal muscle could be related to induction of type 2 diabetes, in which insulin insensitivity occurs in glucose-utilising tissues while being betacells functional. "
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    ABSTRACT: Abstract This experiment was aimed at elucidating the protective effect of resveratrol against diabetes. Forty male Wistar albino rats were allocated into four groups: the control and streptozotocin (STZ)-induced diabetes groups were treated either with placebo (1 ml/kg, i.p.) or resveratrol (20 mg/kg, i.p.) for 8 weeks. Body weight, blood glucose and serum malondialdehyde (MDA) concentrations were monitored. At the end of the experimental period, expression levels of visfatin, sirtuin-1 (SIRT1) and glucose transporters (GLUTs, 2 and 4) were measured in skeletal muscle and pancreas by Western blotting. The resveratrol treatment partially compensated for body weight loss and alleviated hyperglycaemia and returned serum MDA concentrations to the control group levels. Data suggest that supplementation may reduce the severity of diabetes and its complications through suppressing oxidative stress and increasing potential to internalise glucose by extrahepatic tissues.
    International Journal of Food Sciences and Nutrition 02/2015; 66(3):1-7. DOI:10.3109/09637486.2014.1003534 · 1.21 Impact Factor
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