Opposite regulation of hypothalamic orexin and neuropeptide Y receptors and peptide expressions in obese Zucker rats

Many hyothalamic neuropeptides are involved in the regulation of food intak e and body weight. The orexins (OX) which are synthesized in the lateral hy pothalamus are among the most recently characterized whereas neuropeptide Y (NPY) belongs to a group of "older" peptides extensively studied for their effects on feeding behavior. Both stimulate food ingestion in rodents. In this experiment, we measured the expressions of these peptides as well as o f their receptors (OX1-R and OX2-R, Y1 and Y5) in the hypothalamus of obese hyperphagic and lean Zucker rats by real-time RT-PCR using the TaqMan appa ratus. NPY mRNA expression in the obese rats was significantly increased by a factor of 10 (P<0.002) whereas expressions of the Y1 and Y5 receptors we re decreased by 25% (P<0.01) and 50% (P<0.002), respectively. Their prepro- orexin mRNA expression was more than twofold decreased (P<0.01) and express ions of their OX receptors 1 and 2 mRNA were five- and fourfold increased ( P<0.05), respectively. An inverse phenomenon was therefore noted between th e two peptides: for NPY, increased levels and downregulation of receptors; and for OX, diminished levels with upregulation of receptors. The reasons f or these changes might be linked to the absence of leptin signaling as simi lar profiles are found in the ob/ob mice. For orexins at least, other facto rs such as hyperglycemia might be involved. Based on anatomical considerati ons, a direct effect of NPY or of other brain peptides such as CRH cannot b e excluded. We conclude that the diminution in the OX tone might participat e in a counterregulatory system necessary to limit the noxious effects of N PY on food intake and body weight. (C) 2001 Academic Press.