The Divergent Effects of Central and Peripheral Leptin Injections on Feeding and Hypothalamic Neuropeptide Y (NPY) mRNA in Lean and Fatty Zucker Rats

Abstract

fmol/mg I protein/lh) 1 Control 8.9 7.1 41.0 8.1 ACTH 124.0 .+ 41.2" 62.4 + 2.2. *p<0.05Our results suggest that the adrenal gland secretes OLS, the secretion of which appears to be influenced by the secretogogues ACTH and A11 by an, as yet unknown. mechanism. ErratumM15 Welham et al.Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express NPY. a powerful inducer of feeding and obesity. These NPY neurons express the OB-Rb leptin receptor and are overactive in the fatty (fdfa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and NPY neuronal activity is not fully known. We compared the effects of intracerebroventricular (ICV) and intraperitoneal (IP) injection of 3 doses of leptin on food intake and hypothalamic NPY mRNA, in lean and fatty Zucker rats.In lean rats, 4-hr food intake was significantly reduced (p<O.Ol) in a dose-related fashion by up to 40%. by leptin do$es of 2, 10 and 20 pg given ICV and by IP doses of 100 and 200 pg. Hypothalamic NPY mRNA levels after the highest ICV and IP dosages were reduced by 28% and 21% respectively (both p<O.Ol). In fatty rats, ICV injection of 20 pg reduced food intake by 22% (p<O.Ol). but lower ICV dosages and all IP dosages had no e f f a . Hypothalamic NPY mRNA levels were 100% higher in fatty rats than in lean animals. and were reduced by 18% (m.01) after 20 pg leptin ICV. but were unaffected by 200 pg IP.The Ma Zucker rat is therefore less sensitive to leptin given ICV and particularly IP. suggesting that the fa mutation interferes both with leptin's direct effects on neurones and its transport into the CNS. Obesity in the fdki Zucker rat may be partly due to the inability of leptin to inhibR hypothalamic NPY neurones.Plasma volume did not differ between dietary groups at day 14 of gestation (P=0.117).