The tubby mouse is characterized by an autosomal recessive mutation which results in the development of maturity-onset obesity and sensorineural hearing loss and retinal degeneration. Although the tubby mutation which leads to a splicing defect of the tub gene has been identified recently, the mechanism by which it causes the obesity syndrome has not been established. In this study, the potential dysfunction of several hypothalamic neuroendocrine pathways involved in the central regulation of energy metabolism was investigated in tubby mice. In comparison with the wild-type controls, a significant reduction (20%) of pro-opiomelanocortin (POMC) mRNA expression was observed in the arcuate nucleus (ARC) of the mature, obese but not in the juvenile, non-obese tubby mice. Similarly, an age and body mass-dependent induction (about 30-fold) of neuropeptide Y (NPY) mRNA was observed in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of the tubby mice. However, NPY mRNA in the ARC was decreased by approximately 30 to 40% in both juvenile and mature tubby mice. The hypothalamic expression patterns of corticotropin releasing hormone (CRH) and the long form leptin receptor (OB-Rb) were not significantly altered in the mutant mice. These results suggest that the altered hypothalamic POMC and/or NPY functions may be important contributing factors for the development of obesity in this animal model.