It has been suggested that there is an association between increased consumption of high fructose corn syrup and the recent increase in the incidence of obesity. Leptin, an adipose tissue-derived cytokine, inhibits food intake and increases energy expenditure in rodents by crossing the blood brain barrier and activating leptin receptors in the forebrain. Banks et al. (2004) reported that elevated triglyceride levels inhibit leptin transport and a high fructose diet increases post-prandial triglycerides. Therefore, we tested whether consumption of a high-fructose diet (HFruc: 60% kcal fructose) would induce leptin resistance in Sprague—Dawley rats. Post-prandial serum triglycerides were increased by 75% in rats fed HFruc diet for 3 weeks compared with rats fed a fructose-free diet (LFruc). The HFruc and LFruc rats were infused intraperitoneally with either PBS or 60 ìg leptin/day for 2 weeks. Leptin reduced the body fat content LFruc rats by 25% but had no effect in HFruc rats, even though they were less fat than LFruc rats (3% vs. 5% carcass weight). In a second experiment rats fed HFruc or LFruc diets for 4 weeks were injected i.p. with increasing doses of leptin (0, 0.5, 1.0 or 2.5 mg/kg). All doses of leptin inhibited 2 h food intake of LFruc rats but had no effect on intake of HFruc rats. Thus, consumption of a HFruc diet induces leptin resistance, possibly because elevated levels of circulating triglycerides inhibit leptin transport across the blood brain barrier. Supported by Grant R01DK53903 awarded to RBSH.