Central leptin gene therapy blocks ovariectomy-induced adiposity.
OBJECTIVE
In this study, we tested the hypothesis that insufficiency of leptin restraint in the hypothalamus is responsible for promoting weight gain and adiposity after ovariectomy (ovx). Whether increasing leptin transgene expression can overcome the diminution in leptin restraint was evaluated in ovx rats.


METHODS
Enhanced leptin or green fluorescent protein (GFP; control) transgene expression was induced by a single intracerebroventricular injection of recombinant adeno-associated viral vector encoding either leptin gene (rAAV-lep) or GFP gene (rAAV-GFP; control) in acutely and chronically ovx rats. Body weight and food intake responses were monitored weekly. White adipose tissue (WAT) mass and serum levels of WAT-derived hormones, leptin, and adiponectin were analyzed at termination of the experiments.


CONCLUSIONS
An increase in leptin transgene expression in the hypothalamus initiated soon after ovx blocked hyperphagia and body weight gain and markedly suppressed WAT mass and adipokines, leptin, and adiponectin. Similar suppression of weight gain and adiposity and serum leptin and adiponectin levels after intracerebroventricular rAAV-lep injection in chronically ovx rats were observed concomitant with unchanged daily food intake. These findings are consistent with the hypothesis that in the absence of ovarian steroids, the existent insufficiency of leptin restraint at the hypothalamic level can be overcome with ectopic leptin expression, thereby reinstating central control on weight and adiposity.
Torto
Rita
R
Departments of Physiology, University of Florida McKnight Brain Institute, P.O. Box 100244, Gainesville, FL 32610-0244, USA.
Boghossian
Stéphane
S
Dube
Michael G
MG
Kalra
Pushpa S
PS
Kalra
Satya P
SP
D000256:Adenoviridae / Q000235:genetics; D052242:Adiponectin / Q000097:blood; D050154:Adiposity / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D004435:Eating / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism; D007276:Injections, Intraventricular; D007473:Ion Channels / Q000235:genetics; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000502:physiology
D052242:Adiponectin; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000071256:Uncoupling Protein 1