Intake of sodas has been shown to increase energy intake and to contribute to obesity in humans and in animal models, although the magnitude and importance of these effects are still debated. Moreover, intake of sugar sweetened beverages is often associated with high-fat food consumption in humans. We studied two different accesses to a sucrose-sweetened water (SSW, 12.3%, a concentration similar to that usually found in sugar sweetened beverages) in C57BL/6 mice fed a normal-fat (NF) or a high-fat (HF) diet in a scheduled access (7.5 h). NF-fed and HF-fed mice received during 5 weeks access to water, to SSW continuously for 7.5 h (SSW), or to water plus SSW for 2 h (randomly-chosen time slot for only 5 random days/week) (SSW-2h). Mouse preference for SSW was greater in HF-fed mice than NF-fed mice. Continuous SSW access induced weight gain whatever the diet and led to greater caloric intake than mice drinking water in NF-fed mice and in the first three weeks in HF-fed mice. In HF-fed mice, 2 h-intermittent access to SSW induced a greater body weight gain than mice drinking water, and led to hyperphagia on the HF diet when SSW was accessible compared to days without SSW 2 h-access (leading to greater overall caloric intake), possibly through inactivation of the anorexigenic neuropeptide POMC in the hypothalamus. This was not observed in NF-fed mice, but 2 h-intermittent access to SSW stimulated the expression of dopamine, opioid and endocannabinoid receptors in the nucleus accumbens compared to water-access. In conclusion, in mice, a sucrose solution provided 2 h-intermittently and a high-fat diet have combined effects on peripheral and central homeostatic systems involved in food intake regulation, a finding which has significant implications for human obesity. (C) 2014 Elsevier Inc. All rights reserved.