To determine whether leptin resistance caused by a high fructose diet is due to fructose specifically or to increased dietary monosaccharide, we tested leptin responsiveness in rats fed 30% kcal fat diets containing 50% kcal glucose, 40% kcal fructose, or 15% kcal fructose. Intraperitoneal injections of 2.0 mg leptin/kg inhibited 14 hour weight gain and food intake in rats fed 40% fructose or glucose diet for 9 weeks, but not in those fed the 15% fructose diet. Leptin stimulated phosphorylation of signal transducer and activator of transcription 3 (PSTAT-3) in the medial and central nucleus of solitary tract in 40% fructose-fed animals, but not in the hypothalamic arcuate nucleus of any group. In a second study only glucose-fed animals responded to central leptin infusions although all animals remained insulin sensitive. Therefore, dietary monosaccharides may act at sites other than the hypothalamus to reverse high-fat diet induced leptin resistance.