Obesity is frequently associated with leptin resistance. The present study investigated whether leptin resistance in rats is present before obesity develops, and thus could underlie obesity induced by 16 weeks exposure to a liquid, palatable, high-energy diet (HED). Before HED exposure, male Wistar rats (weighing between 330 and 360 g) received i.v infusions of 20 µg of leptin 2h before dark (appr. 57 µg/kg rat). Relative to saline infusion, this caused a highly variable effect on food intake (ranging between -94 and +129%) with food intake suppression that appeared negatively correlated with HED-induced increases in body weight gain, caloric intake, adiposity, and plasma leptin levels. In contrast, leptin's thermogenic response was positively correlated to body weight gain linked to weights of viscera, but not to adiposity. Before HED exposure, leptin unexpectedly increased food intake in some rats (fi+, n=8), whereas others displayed the normal reduction in food intake (fi-, n=7). HED exposed fi+ rats had higher plasma leptin levels, retroperitoneal fat pad weight, HED intake, and body weight gain than fi- and CHOW rats. These parameters were also higher in HED exposed fi- rats relative to CHOW rats, except for plasma leptin concentrations. It is concluded that leptin's reduced efficacy to suppress food intake could predict obesity on a HED. An unexpected orexigenic effect of leptin might potentially contribute to this as well.