The Obese Zucker rat is a model of genetic obesity characterized by hyperphagia, hyperinsulinemia and other endocrine abnormalities. In order to elucidate pathogenetic mechanisms contributing to disturbed feeding behavior in these animals, the effect of food restriction on three hypothalamic neuropeptides involved in the control of food intake was studied. Eighteen male obese and 18 lean Zucker rats were randomly divided into two groups: half of the animals were food-restricted for 2 weeks, while the other half served as controls and were fed ad libitum. The levels of preproneuropeptide Y (preproNPY), preprocorticotropin releasing factor (preproCRF) and preprosomatostatin (preproSOM) mRNAs were determined using in situ hybridization technique. In addition, plasma insulin and corticosterone concentrations were analyzed. Food restriction significantly increased the expression of preproNPY mRNA in the arcuate nucleus in both Zucker phenotypes, while the expressions of preproCRF mRNA in the paraventricular nucleus (PVN) and preproSOM mRNA in the periventricular nucleus (PeV) were not altered. The expression of preproNPY mRNA was significantly greater in control obese animals compared to control lean animals. Food restriction lowered plasma insulin levels, but did not change plasma corticosterone levels. It is concluded that food restriction specifically activates NPY gene transcription in the arcuate nucleus the response being similar in both Zucker phenotypes. The results suggest that orexigenic NPY plays a role in the adaptation to altered feeding status.