期刊
REGULATORY PEPTIDES
卷 92, 期 1-3, 页码 97-105出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0167-0115(00)00155-5
关键词
gene therapy; NPY; AgrP; POMC; leptin; hypothalamus
资金
- NIDDK NIH HHS [DK37273] Funding Source: Medline
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 (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 observation. A ten-fold higher dose (6 x 10(11) particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-beta Ob 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, alpha -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-beta Ob 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. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据