title: Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Revollo
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Mills
authors.forename: Akiko
authors.initials: A
authors.lastname: Satoh
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Antje
authors.initials: A
authors.lastname: Garten
authors.forename: Biplab
authors.initials: B
authors.lastname: Dasgupta
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolberger
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Imai
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D018149:Glucose Intolerance; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000096:biosynthesis*; D009537:Nicotinamide Mononucleotide / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase