SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice.
Nicotinamide phosphoribosyltransferase (NAMPT), the key NAD(+) biosynthetic enzyme, has two different forms, intra- and extracellular (iNAMPT and eNAMPT), in mammals. However, the significance of eNAMPT secretion remains unclear. Here we demonstrate that deacetylation of iNAMPT by the mammalian NAD(+)-dependent deacetylase SIRT1 predisposes the protein to secretion in adipocytes. NAMPT mutants reveal that SIRT1 deacetylates lysine 53 (K53) and enhances eNAMPT activity and secretion. Adipose tissue-specific Nampt knockout and knockin (ANKO and ANKI) mice show reciprocal changes in circulating eNAMPT, affecting hypothalamic NAD(+)/SIRT1 signaling and physical activity accordingly. The defect in physical activity observed in ANKO mice is ameliorated by nicotinamide mononucleotide (NMN). Furthermore, administration of a NAMPT-neutralizing antibody decreases hypothalamic NAD(+) production, and treating ex vivo hypothalamic explants with purified eNAMPT enhances NAD(+), SIRT1 activity, and neural activation. Thus, our findings indicate a critical role of adipose tissue as a modulator for the regulation of NAD(+) biosynthesis at a systemic level.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Myeong Jin
MJ
Yoon
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mitsukuni
M
Yoshida
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sean
S
Johnson
The First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
Akiko
A
Takikawa
The First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
Isao
I
Usui
The First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan.
Kazuyuki
K
Tobe
Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan.
Takashi
T
Nakagawa
Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jun
J
Yoshino
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: imaishin@wustl.edu.
Shin-ichiro
S
Imai
D000107:Acetylation; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1