Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.