The hypothalamus is the brain center that controls the energy balance. The arcuate nucleus of the hypothalamus contains two distinct types of neurons, anorexigenic POMC neurons and orexigenic AgRP neurons. FoxO1 is a transcription factor regulated by insulin signaling that is deacetylated by Sirt1, a nicotinamide adenine dinucleotide- (NAD⁺) dependent deacetylase. FoxO1 overexpression in POMC neurons leads to obesity, whereas Sirt1 overexpression leads to leanness. Here we tested whether overexpression of Sirt1 in POMC neurons could rescue the obese phenotype of POMC neuron-specific constitutively-nuclear FoxO1 (CN-FoxO1) knock-in (KI) mice by analyzing POMC neuron-specific CN-FoxO1/Sirt1 double-KI (DKI) mice. The obese phenotype of CN-FoxO1 KI mice was rescued in male DKI mice. A trend for decreased O₂ consumption, increased adiposity, and fewer POMC neurons in CN-FoxO1 mice was partially rescued in male DKI mice. Food intake and locomotor activity were not altered. Sirt1 overexpression decreased FoxO1 acetylation and protein levels without affecting CN-FoxO1 nuclear localization in mouse embryonic fibroblasts and hypothalamic N41 cells. Based on these results, we conclude that Sirt1 overexpression in POMC neurons partially rescued obesity caused by CN-Foxo1 by decreasing FoxO1 acetylation and FoxO1 protein levels. Further, Sirt1 partially reversed obesity due to central insulin resistance in male mice.