Abstract
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 x 109 particles) was ineffective, the middle dose (6 x 1010 particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6 x 1011 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. (C) 2000 Elsevier Science B.V.
Original language | English (US) |
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Pages (from-to) | 97-105 |
Number of pages | 9 |
Journal | Regulatory Peptides |
Volume | 92 |
Issue number | 1-3 |
DOIs | |
State | Published - Aug 25 2000 |
Keywords
- AgrP
- Gene Therapy
- Hypothalamus
- Leptin
- NPY
- POMC
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Endocrinology
- Clinical Biochemistry
- Cellular and Molecular Neuroscience