We investigated the role of zinc in food intake regulation using rats during early-stage zinc deficiency without decreased zinc concentrations in plasma and tissues. Plasma, liver, and hypothalamic zinc concentrations were not affected in male Sprague-Dawley rats fed a zinc-deficient (Zn-Def) diet for 3 d compared with the pair-fed control group, which was fed a zinc-sufficient diet to the intake of the Zn-Def diet. Zinc sulfate at a dose of 19 micromol/kg body weight was orally or intraperitoneally (i.p.) administered to rats fed a Zn-Def diet for 3d and food intake was measured. We found that zinc stimulated food intake after oral but not i.p. administration. The mRNA expression of neuropeptide Y (NPY) and orexin in the hypothalamus significantly increased 3 h after oral but not i.p. administration of zinc. Pretreatment with an antagonist for the NPY Y(1) receptor or the orexin OX(1) receptor blocked orexigenic activity after oral administration of zinc. The stimulation of food intake by oral administration of zinc was abolished by vagotomy. Taken together, orally administered zinc may stimulate food intake via orexigenic peptides coupled to the afferent vagal stimulation in rats after short-term treatment with a Zn-Def diet.