Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus.
We have examined the dose-dependent effects and central action of intraventricular administration of a recombinant adeno-associated virus encoding rat leptin (rAAV-leptin) in suppressing body weight (BW) gain in adult female rats. A low dose of rAAV-leptin (5x10(10) particles) suppressed weight gain (15%) without changing daily food intake (FI), but a twofold higher dose decreased BW by 30% along with a reduction in daily FI. Reduced BW was due to a loss in body adiposity because serum leptin was reduced. Serum insulin levels were decreased (96%) by only the high dose along with a slight reduction in glucose. Uncoupling protein-1 (UCP-1) mRNA expression in brown adipose tissue (BAT), reflecting energy expenditure through thermogenesis, was upregulated to the same magnitude by the two rAAV-leptin doses. We analyzed by in situ hybridization the expression in the hypothalamus of genes encoding the appetite-regulating neuropeptides. Only the high dose decreased expression of neuropeptide Y (NPY), the orexigenic peptide, and increased proopiomelanocortin (POMC), precursor of the an orexigenic peptide, alpha-MSH. Our studies show for the first time that increased availability of leptin within the hypothalamus through central leptin gene therapy dose-dependently decreases weight gain, adiposity, and serum insulin by increasing energy expenditure and decreasing FI. The decrease in FI occurs only when NPY is reduced and alpha-MSH is increased in the hypothalamus by the high dose of rAAV-leptin. Delivery of the leptin gene centrally through rAAV vectors is a viable therapeutic modality for long-term control of weight and metabolic hormones.
Dhillon
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Department of Physiology, University of Florida McKnight Brain Institute, College of Medicine, Gainesville, Florida 32610, USA.
Kalra
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Kalra
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D054369:Agouti-Related Protein; D000818:Animals; D001066:Appetite; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071256:Uncoupling Protein 1
D054369:Agouti-Related Protein; D002352:Carrier Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009478:Neuropeptide Y; D011506:Proteins; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D011333:Pro-Opiomelanocortin