Excessive dietary intake of carbohydrates and fats has been linked to the development of obesity. However, the mechanism by which these dietary factors interact to bring about metabolic changes has not been elucidated. We examined the combined effects of different types of dietary carbohydrates and fats on the etiology of obesity and its complications in the Zucker fatty (fa/fa) rat, a model of obesity. Specifically, these rats were fed an isocaloric diet containing various combinations of carbohydrates [palatinose (P), an insulin-sparing sucrose analogue, and sucrose (S)] and fatty acids [oleic acid (O) and linoleic acid (L)]. After 8 wk, palatinose feeding (PO and PL) led to significant reductions in visceral fat mass, adipocyte cell size, hyperglycemia, and hyperlipidemia compared with sucrose feeding (SO and SL); pancreatic islet hypertrophy was also prevented by palatinose feeding. Linoleic-acid-fed rats (PL and SL) exhibited reduced insulin-immunoreactive staining of the pancreatic islets, enhanced macrophage infiltration in adipose tissue, and an elevated plasma tumor necrosis factor-alpha concentration when compared with oleic-acid-fed rats (PO and SO). Furthermore, sucrose and linoleic acid synergistically increased the expression of genes involved in hepatic gluconeogenesis and lipogenesis [sterol regulatory-element binding protein (SREBP)-1c and SREBP-2]. In conclusion, a diet containing palatinose and oleic acid may prevent diet-induced metabolic abnormalities. The combination of palatinose and oleic acid holds promise for a new approach to preventing and treating obesity and its complications.