Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains discussed and that of orexigenic and anorexigenic hypothalamic neuropeptides unknown. The present study was designed to address this issue using obese (Lepr^fa/Lepr^fa) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygotous lean (Lepr^FA/Lepr^FA) and obese (Lepr^fa/Lepr^fa) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2 or 4 days (barometric pressure, 505hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue using real-time quantitative PCR analysis, and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38% and 67% of initial values at day 1, respectively, P<0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic NPY levels in lean rats 2 days after hypoxia exposure contributed to account for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorexic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.