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. Yoon et al. shed light on the two forms of the NAD⁺ biosynthetic enzyme, intra- and extracellular NAMPT. SIRT1-mediated deacetylation of iNAMPT promotes its extracellular secretion from adipocytes. eNAMPT, in turn, affects NAD⁺/SIRT1 signaling in the hypothalamus, with effects on physical activity, implicating adipose tissue as a systemic NAD⁺ modulator.