We assessed the effect of early onset exercise as a means of preventing childhood obesity using juvenile male rats selectively bred to develop diet-induced obesity (DIO) or to be diet-resistant (DR) when fed a 31% fat high energy (HE) diet. Voluntary wheel running begun at 36 d of age selectively reduced adiposity in DIO vs. DR rats. Other 4 wk old DIO rats fed HE diet and exercised (Ex) for 13 wk increased their core temperature, gained 22% less body weight and had 39% lighter fat pads when compared to sedentary (Sed) rats. When wheels were removed after 6 wk (6 wk Ex/7 wk Sed), rats gained less body weight over the next 7 wk than Sed rats and still had comparable adipose pad weights to 13wk exercised rats. In fact, only 3 wk of exercise sufficed to prevent obesity for 10wk after wheel removal. Terminally, the 6 wk Ex/7 wk Sed rats had a 55% increase in arcuate nucleus proopiomelanocortin mRNA expression vs. Sed rats suggesting that this contributed to their sustained obesity resistance. Finally, when Sed rats were calorically restricted for 6 wk to weight match them to Ex rats (6 wk Rstr/7 wk Al), they increased their intake and body weight when fed ad libitum and, after 7 wk more, had higher leptin levels and adiposity than Sed rats. Thus, early onset exercise may favorably alter, while early caloric restriction may unfavorably influence the development of the hypothalamic pathways controlling energy homeostasis during brain development.