We previously showed that if 4-week old rats bred to develop diet-induced obesity (DIO) exercised in a running wheel for only 3 weeks (Ex), they did not become obese on a 31% fat diet for another 10 weeks of remaining sedentary (Sed). We postulated that increased leptin sensitivity caused this resistance to weight regain. In fact, while Sed rats had no response to leptin, (5 mg/kg, i.p.), DIO rats exercised for 3 week ate 36% less in 24 h (11.9+1.1 g) than their baseline intake (18.6+0.8g; P=0.001) and had a 23% increase in the number of arcuate nucleus neurons expressing pSTAT3 following leptin treatment. Furthermore, their increased leptin sensitivity persisted 4 weeks after exercise termination (3 weeksEx/ 4 weeksSed); rats left Sed for 7 weeks still had no response to leptin, while 3 weekEx/4 weekSed rats at 24% less (20.1+1.4g) after leptin than their 24 h baselines (26.6+1.0 g; P=0.001). However, increased leptin sensitivity was not responsible for the long-term reduction in body fat, since neither 13 weeks Sed nor rats exercised for 3 weeks and held Sed for 10 weeks responded to the anorectic effects of leptin, despite the fact that the latter maintained lower carcass adiposity. These data suggest that, 3 weeks of post-weaning exercise lowers the defended body weight in leptin-resistant DIO rats by increasing their leptin sensitivity for several weeks after exercise cessation. However, this increased sensitivity alone cannot fully explain their long-term resistance to obesity. We postulate that early onset exercise increases in leptin sensitivity may promote this long-term effect by favorably altering the development of neural pathways involved in energy homeostasis.