Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme in a broad range of biological functions including transcriptional regulation via NAD- dependent deacetylase sirtuins. Intracellular NAD is produced through denovosynthesisorviasalvagepathways. Nicotinamide phosphoribosyltransferase (Nampt), also known as visfatin or pre-B cell enhancing factor (PBEF), catalyses a rate-limiting step in the NAD salvage pathway. We investigated a potential involvement of Visfatin/eNampt in central regulation of energy balance. Central and peripheral administration of the Nampt peptide (extracellular Nampt/eNampt) and a Nampt enzymatic product nicotinamide mononucleotide (NMN) inhibited food intake and weight gain in mice. In contrast, administration of the Nampt inhibitor FK866 resulted in hyperphagia and blocked eNampt-induced anorexia and weight loss, suggesting that enhanced Nampt activity produces a negative energy balance. Interestingly, central and peripheral administration of Nampt increased NAD in hypothalamus, liver, blood. In the hypothalamic neurons, treatment with eNampt and NMN strongly promoted the nuclear export and degradation of the transcription factor Foxo1, thereby repressing its transcriptional activities on genes encoding key appetite-regulating neuropeptides such as neuropeptide Y, Agouti-related protein and proopiomelanocortin. Moreover, these effects were mediated through Sirt2-induced Foxo1 deacetylation. Together, these findings indicate that eNampt modulates body weight metabolism by regulating hypothalamic Sirt2 and Foxo1 activities. Nampt is a critical regulator in the circadian clock machinery. Notably, plasma eNampt levels displayed a circadian rhythm with a nocturnal rise in mice, which was reciprocal to the circadian changes in hypothalamic Foxo1 levels. Therefore, eNampt may function as an important molecular link between the circadian and metabolic systems.