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

• Published in: Regulatory peptides 2000-08, Vol.92 (1), p.97-105
• Main Authors: Dhillon, H, Ge, Y.-L, Minter, R.M, Prima, V, Moldawer, L.L, Muzyczka, N, Zolotukhin, S, Kalra, P.S, Kalra, S.P
• Format: Article
• Language: English
• Subjects: Agouti-Related Protein; AgrP; alpha-MSH - genetics; Animals; Body Weight; Dependovirus; Gene Expression Regulation; Gene Therapy; Genetic Vectors; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leptin; Leptin - blood; Leptin - genetics; Leptin - metabolism; Male; Mice; Mice, Obese; Nerve Tissue Proteins - genetics; Neuropeptide Y - genetics; NPY; POMC; Pro-Opiomelanocortin - genetics; Proteins - genetics; Time Factors
• ISSN: 0167-0115; 1873-1686
• DOI: 10.1016/S0167-0115(00)00155-5

We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (βOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-βOb (6×10 9 particles) was ineffective, the middle dose (6×10 10 particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6×10 11 particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-βOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, α-melanocyte stimulating hormone and cocaine-and-amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-βOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic 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 therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood–brain barrier to ameliorate neuroendocrine disorders.