Loss of body fat in leptin-treated animals has been attributed to reduced energy intake, increased thermogenesis and preferential fatty acid oxidation. Leptin does not decrease food intake or body fat in leptin-resistant high fat (HF) fed mice, possibly due to a failure of leptin to activate hypothalamic receptors. We measured energy expenditure of male C57BL/6 mice adapted to LF or HF diet and infused them for 13 days with PBS or 10 ug leptin/day from an intraperitoneal miniosmotic pump to test whether leptin resistance prevented leptin-induced increases in energy expenditure and fatty acid oxidation. There was no effect of low dose leptin infusions on either of these measures in LF-fed or HF-fed mice even though LF-fed mice lost body fat. Experiment 2 tested leptin responsiveness in LF-fed and HF-fed mice housed at different temperatures (18°C, 23°C, 27°C), assuming that the cold would increase and the hot environment would inhibit food intake and thermogenesis which could potentially interfere with leptin action. LF-fed mice housed at 23°C were the only mice that lost body fat during leptin infusion, suggesting that an ability to modify energy expenditure is essential to the maintenance of leptin-responsiveness. HF-fed mice in cold or warm environments did not respond to leptin. HF-fed mice in the hot environment were fatter than other HF-fed mice and, surprisingly, leptin caused a further increase in body fat, demonstrating that the mice were not totally leptin resistant and that partial leptin resistance in a hot environment favors positive energy balance and fat deposition.