Single intracerebroventricular bolus injection of a recombinant adenovirusexpressing leptin results in reduction of food intake and body weight in both lean and obese Zucker fa/fa rats

Leptin acts as a satiety factor within the central nervous system by bindin g to its receptor located in the hypothalamus. A missense mutation of the l eptin receptor induces hyperphagia and obesity in the obese Zucker fa/fa ra t. Since the CNS is an important target of leptin action, we hypothesized t hat leptin gene transfer into the lateral cerebral ventricle could efficien tly lead to inhibition of food intake and reduction of body weight in obese fa/fa rats as well as in lean animals. A single intracerebroventricular in jection of an adenoviral vector containing a cDNA encoding leptin resulted in the expression of leptin in the ependymal cells lining the ventricle and the secretion of leptin into the cerebrospinal fluid (CSF). During the fir st week after injection, when high concentrations of leptin were produced i n the CSF, the reducing effects of leptin on food intake and body weight we re comparable in lean and in obese fa/fa rats. The subsequent decline in CS F leptin levels, that was similar in lean and obese fa/fa rats, resulted in the faster resumption of food intake and body weight gain in obese than in lean animals, confirming a reduced sensitivity to leptin in the obese grou p. The results of this study show that leptin gene delivery into the cerebr al ventricles allows for the production of elevated leptin concentrations i n CSF, and they support the hypothesis that the impaired sensitivity to lep tin may be overcome in obese fa/fa rats. (C) 2000 Elsevier Science B.V. All rights reserved.