The relation between dietary fructose, dietary fat and leptin responsiveness in rats

► Rats fed a low fat (10% kcal), very high fructose (60% kcal) diet for 3 weeks were resistant to peripheral, but not central leptin administration. ► The peripheral leptin resistance was not caused by a failure of leptin to cross the blood brain barrier because peripheral leptin increased hypothalamic phosphorylation of STAT3. ► Rats fed a low fructose (18% kcal), high fat (30% kcal) diet for 64 days were resistant to peripheral leptin, but leptin resistance was prevented in rats fed a high fat diet containing 40% kcal fructose although percent body fat was not changed. ► Replacement of fructose with glucose in the high fat diet also prevented development of leptin resistance. ► These results suggest that dietary monosaccharides modify a metabolic process that influences the effects of leptin on food intake and weight gain.