Others reported that rats fed a high-fructose diet for 6 months were leptin resistant. We tested peripheral and/or central leptin responses in rats fed fructose for shorter time periods. Rats fed a diet containing 60% energy (% kcal) fructose and 10% kcal fat diet for 21 days had the same serum triglycerides (TG), gained less weight than controls, decreased their food intake and weight gain in response to central injections of 0.5 or 1.0 ug leptin, but were resistant to an i.p. injection of 2.0 mg leptin/kg. An i.p. injection of 1 mg leptin/kg increased phosphorylation of hypothalamic signal transducer and activator of transcription 3 (PSTAT3) implying resistance was not a failure of leptin to cross the blood brain barrier. The effects of dietary fructose were compared with those of dietary fat. Rats fed a 10%kcal fructose and 30%kcal fat diet for 39 days were leptin resistant whereas rats fed a 40%kcal fructose and 30%kcal fat diet responded to i.p. leptin. Another monosaccharide, glucose, replicated the effects of fructose in the 30% kcal fat diet. Surprisingly, none of the rats showed a reliable response to third ventricle leptin and peripheral leptin failed to stimulate hypothalamic PSTAT3 although it did increase PSTAT3 in the brainstem of rats fed the 40%kcal fructose or glucose diets. Thus a high-fructose, low-fat diet induces peripheral leptin resistance in less than 4 weeks, but high dietary concentrations of fructose or glucose prevent peripheral leptin resistance in rats fed a high-fat diet.