Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice - Relationship with body weight change

We investigated the long-term effects of physiological levels of leptin pro duced by gene therapy on body weight (BW) and expression of genes that enco de orexigenic and anorexigenic peptides in the hypothalamus. Recombinant ad eno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic ve ctor, encoding leptin (beta Ob) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-beta Ob (6 X 10(9) particles) was ineffective, the middle dose (6 X 10(10) particles) curbed BW gain without affecting food consumption for 75 days of observatio n. A ten-fold higher dose (6 x 10(11) particles) resulted in increased bloo d leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-beta Ob doses that either curbed BW w ithout affecting food consumption or evoked BW loss and reduced food intake , decreased the expression of genes encoding the orexigenic peptides, neuro peptide Y and agouti-related peptide in the ARC, and the two doses were equ ally effective. Concomitantly, the expression of genes encoding the anorexi genic peptide, alpha -melanocyte stimulating hormone and cocaine-and-amphet amine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of deliverin g biologically active leptin for extended periods by an iv injection of rAA V-beta Ob and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on a norexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene ther apy is an effective mode of delivery to the hypothalamus of those therapeut ic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders. (C) 2000 Elsevier Science B.V. All rights reserved.