The Weight-Reducing Effect of an Intracerebroventricular Bolus Injection of Leptin in Genetically Obese fa/fa Rats: Reduced Sensitivity Compared With Lean Animals

The effect of different doses of leptin, given as an intracerebroventricular (ICV) bolus, on body weight gain and food intake was investigated during refeeding, following a 24-h fast in lean (FA/fa) rats. It was observed that ICV leptin resulted in a dose-dependent decrease in body weight gain, compared with vehicle injection, a difference that persisted for at least 6 days. This was associated with a transient reduction in food intake over the first 2 days after leptin injection. More importantly, the effect of leptin was also observed in genetically obese fa/fa rats but at the expense of two to ten times higher leptin concentrations, indicating the presence of decreased leptin sensitivity. Furthermore, ICV leptin injections were able to decrease neuropeptide Y (NPY) levels in the arcuate and paraventricular hypothalamic nuclei in both lean and genetically obese fa/fa rats, although a higher leptin dose was again needed in the obese group. These observations provide further evidence for the implication of NPY and leptin in a regulatory loop controlling body homeostasis. This loop is functional in lean and genetically obese fa/fa rats, provided that leptin levels in the central nervous system are high enough in the obese group, in particular. Since human obesity is frequently associated with elevated circulating leptin levels, a state of decreased leptin sensitivity (i.e., leptin resistance), similar to that described here in fa/fa rats, could possibly occur in human syndromes as well.