Evidence that hypothalamic neurotensin signals leptin effects on feeding behavior in normal and fat-preferring rats

Leptin inhibits food intake when it is injected in the periphery or in the central nervous system. It is Likely that its action is not only mediated b y the inhibition of orexigenic peptides such as neuropeptide Y. Therefore, we characterized the pharmacological and physiological relationships of lep tin with neurotensin (NT), a central feeding inhibitor. Firstly, we investi gated the central interactions of leptin and NT. Intracerebro-ventricular ( ICV) injection were done in normal Long-Evans rats. NT had a short lasting (30 minutes; p<0.01) inhibitory effect on spontaneous food intake measured at the beginning of the dark phase whereas the effect of ICV leptin was obs erved after 24 hours (p<0.001). Coinjection with leptin potentiated NT effe ct at 30 minutes (p<0.001) and prolonged it for 30 additional minutes (p<0. 01). In addition, NT potentiated the effect of leptin at 30 and 60 minutes (p<0.02 and p<0.001 respectively) but not at 24 hours. Secondly, we observe d that NT concentrations were augmented in selective brain areas in fat-pre ferring rats (+ 34% for hypothalamic NT; p<0.03). This increase was observe d in the parvocellular part of the paraventricular nucleus (PVNp) only and was associated with an increase in circulating leptin levels (+ 75% p<0.003 ). Interestingly, plasma leptin and NT in the PVNp were strongly correlated (r=0.57; p<0.003), suggesting changes of NT processing or release in this nucleus. These results strongly suggest that the short-term anorexigenic ef fects of leptin in normal rats are at least partly mediated by changes in N T processing or release. They also suggest that these processes take place in the hypothalamus, most probably in the PVNp and that they might be sensi tive to fat ingestion. Therefore, the neurotensin increase observed in fat- preferring rats would limit the overconsumption of energy, a physiological mechanism translated by leptin. (C) 1998 Academic Press.