Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study

The weight-reducing effects of leptin are predominantly mediated through th e hypothalamus in the brain. Gene therapy strategies designed for weight co ntrol have so far tested the short-term effect of peripherally delivered vi ral vectors encoding the leptin gene. In order to circumvent the multiple p eripheral effects of hyperleptinemia and to overcome the age-related develo pment of leptin resistance due to multiple factors, including defective lep tin transport across the blood brain barrier, we determined whether deliver y of viral vectors directly into the brain is a viable therapeutic strategy for long-term weight control in normal wild-type rats. A recombinant adeno -associated virus (rAAV) vector encoding rat leptin (Ob) cDNA was generated (rAAV-beta Ob). When administered once intracerebroventricularly (i.c.v.), rAAV-beta Ob suppressed the normal time-related weight gain for extended p eriods of time in adult Sprague-Dawley rats. The vector expression was conf irmed by immunocytochemical localization of GFP and RT-PCR analysis of lept in in the hypothalamus. This sustained restraint on weight gain was not due to shifts in caloric consumption because food-intake was similar in rAAV-b eta Ob-treated and rAAV-GFP-treated control rats throughout the experiment. Weight gain suppression, first apparent after 2 weeks, was a result of red uced white fat depots and was accompanied by drastically reduced serum lept in and insulin concentrations in conjunction with normoglycemia. Additional ly, there was a marked increase in uncoupling protein-1 (UCP1) mRNA express ion in brown adipose tissue, thereby indicating increased energy expenditur e through thermogenesis. Seemingly, a selective enhancement in energy expen diture following central delivery of the leptin gene is a viable therapeuti c strategy to control the age-related weight gain and provide protection fr om the accompanying multiple peripheral effects of hyperleptinemia and hype rinsulinemia. (C) 2001 Elsevier Science B.V. All rights reserved.