Overnutrition during the suckling period (small litter, SL) results in the development of adult-onset obesity. Our aim was to investigate if two levels of caloric restriction (CR) in the early postweaning period can reverse obese phenotype in SL rats. The normal litter (NL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until 21. After weaning rats consumed lab-chow as indicated: (i) NL and SL groups were on ad libitum regimen up to day 140, (ii) another SL group was pair-fed (SL/PF) to NL(~14% reduction), (iii) SL/PF/AL group was pair-fed up to day 94 and then switched to ad libitum feeding, (iv) SL/CR group received 24% reduction (moderate CR) in food intake compared to SL, and (v) SL/CR/AL group was on 24% CR up to day 94 and then switched to ad libitum feeding. Pair-feeding reduced body weight gains and serum insulin and leptin levels compared to SL rats, but these parameters were restored to SL levels in the SL/PF/AL rats after switching to ad libitum feeding. Interestingly, the moderate CR normalized these parameters in SL/CR and SL/CR/AL rats compared to NL. The expression of neuropeptide Y, pro-opiomelanocortin and leptin receptor returned to control levels in the hypothalami from SL/CR and SL/CR/AL rats. These results indicate that appropriate manipulation of energy intake during the early postweaning period could lead to longer lasting effects on the regulation of body weight homeostasis via reversal of the early preweaning programming effects on the hypothalamic appetite regulation mechanism.