Silent information regulator (SIR)2 is an nicotinamide adenine dinucleotide dependent deacetylase implicated in the regulation of life span in species as diverse as yeast, worms, and flies. Mammalian Sirt1 is the most closely related homolog of the SIR2 gene. Pharmacological activators of Sirt1 have been reported to increase the life span and improve the health of mice fed a high-fat diet and to reverse diabetes in rodents. Sirt1 links the energy availability status with cellular metabolism in peripheral organs including liver, pancreas, muscle, and white adipose tissue. Insulin and leptin signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus via Forkhead box O (Foxo)-1 and signal transducer and activator of transcription-3. Sirt1 has been reported to improve insulin sensitivity in vitro, but the role of hypothalamic Sirt1 in regulating feeding has not been addressed. We found that hypothalamic Sirt1 protein levels increase on feeding, and this induction is abrogated in diet-induced obese mice and db/db mice. We also demonstrate for the first time that Sirt1 protein turnover is regulated by the proteasome and ubiquitination in a hypothalamic cell line and in vivo by feeding, and this regulation is not seen in a pituitary cell line AtT20. Forced expression of wild-type Sirt1 in the mediobasal hypothalamus by adenovirus microinjection suppressed Foxo1-induced hyperphagia, a model for central insulin resistance. Moreover, Sirt1 suppressed Foxo1-dependent expression of the orexigenic neuropeptide Agouti-related peptide in vitro. We propose that on feeding, Sirt1 protein is stabilized in the hypothalamus, leading to decreased Foxo1-dependent expression of orexigenic neuropeptide Agouti-related peptide and cessation of feeding.