Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme.
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.
Revollo
Javier R
JR
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Körner
Antje
A
Mills
Kathryn F
KF
Satoh
Akiko
A
Wang
Tao
T
Garten
Antje
A
Dasgupta
Biplab
B
Sasaki
Yo
Y
Wolberger
Cynthia
C
Townsend
R Reid
RR
Milbrandt
Jeffrey
J
Kiess
Wieland
W
Imai
Shin-Ichiro
S
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
D007328:Insulin; D009243:NAD; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase