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 rats were fed either an HFS or LFCC diet ad libitum for a period of 20 months. Measurements of leptin concentration, insulin concentration and adipocyte size were performed at 2 weeks, 2 months, 6 months and 20 months. 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 months of the dietary intervention. Plasma leptin and insulin concentrations were significantly elevated within 2 weeks of HFS diet consumption and remained elevated throughout the course of the study. After 2 months, the HFS adipocytes 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, resulting from a higher feed efficiency. There were no significant differences in body temperature or activity levels between the groups. These results demonstrate that an 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.