The aim of this study was to determine the effects of the chronic ingestion of aspartame (ASP) on brain neuropeptide Y (NPY) concentrations, plasma hormones, food intake and body fat. Two groups of male Long-Evans rats, fed on a control (C) well-balanced diet, had to drink either a 0.1% ASP solution or water for a period of 14 weeks starting at weaning. Food intake and body weight were weekly recorded. At the end of the experiment, fat pads were sampled, leptin and insulin were measured in the plasma and NPY in several microdissected brain areas. Substituting ASP for water led to lower body weight (-8%; P<.004) and lower fat depot weight (-20%; P<.01) with no differences in energy intake or plasma insulin concentrations. Plasma leptin was significantly reduced by 34% (P<.05). Leptin concentrations were well-correlated with final body weight (r=.47; P<.025) and fat pad mass (r=.53; P<.01). NPY concentrations were 23% lower (P<.03) in the arcuate nucleus of ASP rats with no differences in other brain areas. The beneficial effects on body composition could be related to the decreased effects of NPY on lipid and energy metabolism, independently of insulin. The reasons for the NPY decrease (regulatory or toxicological) are not obvious. The constitutive amino acids of the ASP molecule might participate in the NPY regulation.