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Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans‐activating and trans‐repressing activity of the hepatic peroxisome proliferator‐activated receptor α (PPARα). As a consequence, fructose decreases hepatic fatty oxidation and increases pro‐inflammatory transcription factor nuclear factor κB (NF‐κB) activity. These changes were not observed in glucose‐administered rats (10% wt/vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructose‐fed, but not glucose‐fed, rats were hyperleptinemic and exhibited …