Changes in dietary macronutrient composition and/or CNS neuronal activity can underlie obesity and disturbed fuel homeostasis. Here we examined whether switching rats from high-carbohydrate (HC; i.e., regular chow) feeding to diets with either a high-fat (HF) or a high-fat/high-protein content at expense of carbohydrates (LC-HF-HP), causes differential effects on body weight and glucose homeostasis which depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlied these effects. Chronic third-cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol.d^-1) produced obesity and hyperphagia with an increased food efficiency (FE) again observed during HF (+19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHU9119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold) and adiponectin (2.4-3.7 fold) levels, but diet effects were only observed on plasma adiponectin (HC and LC-HF-HP<HF). Finally, SHU9119-treated LC-HF-HP-fed rats were less glucose tolerant than others. Relatively low plasma adiponectin levels likely contributed to this effect. Thus, HF feeding amplifies obesity induced by impaired MC signaling, provided that the C/P ratio is high enough. Reduction of the C/P ratio within a HF diet ameliorates hyperphagia and obesity in rats with impaired MC signaling, but aggravates associated disturbances in fuel homeostasis.