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 inh ibiting hypothalamic neurons that express neuropeptide Y, a powerful induce r of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb le ptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mu tation affects the extracellular domain of the leptin receptor, but its imp act on leptin action and neuropeptide Y neuronal activity is not fully know n. We compared the effects of three doses of leptin given intracerebroventr icularly and three doses of leptin injected intraperitoneally on food intak e and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In l ean 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 mu g/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21 % after the highest intracerebroventricular and intraperitoneal doses respe ctively (P < 0.01 for both). In fatty rats, only the highest intracerebrove ntricular 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 neuropept ide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin give n intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neuron s and its transport into the central nervous system. Obesity in the fa/fa Z ucker rat may be partly due to the inability of leptin to inhibit hypothala mic neuropeptide Y neurons.