This study investigated the effect of long-term high-fat sucrose (HFS) or low-fat complex-carbohydrate (LFCC) diet consumption on leptin, insulin, fat cell size, energy intake, and markers of activity to ascertain the role that leptin plays in long-term energy balance in a model of diet-induced obesity. Female Fischer 344 rats were fed either a HFS or LFCC diet ad libitum for a period of 20 mo. Measurements of leptin concentration, insulin concentration, and adipocyte size were performed at 2 wk, 2 mo, 6 mo, and 20 mo. Body weight and energy intake were measured weekly for calculation of feed efficiency. Body temperature and activity levels were assessed over a 5-day period after 12 mo of the dietary intervention. Plasma leptin and insulin concentrations were significantly elevated within 2 wk of HFS diet consumption and remained elevated throughout the course of the study. After 2 mo, the adipocytes of the HFS group were significantly larger and continued to increase in size throughout the course of the study. A significant correlation was noted between leptin and adipocyte cell size (r = 0.96, P < 0.01). However, despite elevated leptin, energy intake was similar, and the HFS group weighed significantly more than the LFCC group, as a result of a higher feed efficiency. There were no significant differences in body temperature or activity levels between the groups. These results demonstrate that a HFS diet causes hyperleptinemia and hyperinsulinemia before adipocyte size is increased and suggests that leptin resistance may be present or, alternatively, that leptin does not to play a major role in the long-term regulation of energy intake or activity levels in this model.