Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes.
Intracerebroventricular administration of recombinant adeno-associated virus (rAAV) encoding the rat leptin gene (rAAV-lep) to 24-d-old female and male rats suppressed postpubertal weight gain for extended periods by decreasing food consumption and adiposity, as reflected by lowered serum leptin, insulin, and FFA. Serum ghrelin levels were increased in young but not older rats. Central rAAV-lep therapy also increased energy expenditure through nonshivering thermogenesis in younger rats as shown by expression of uncoupling protein mRNA in brown adipose tissue. The sustained decrease in appetite seemingly resulted from attenuation of appetite-stimulating neuropeptide Y and enhancement of appetite-inhibiting melanocortin signalings in the hypothalamus. Neither the onset of pubertal sexual maturation nor reproductive cyclicity in adult female rats was affected by the sustained reduction in energy consumption and weight gain. These findings demonstrate that central leptin gene therapy in prepubertal rats is a novel therapy to control postpubertal weight gain, adiposity, and hyperinsulinemia for extended periods.
Beretta
Elena
E
Department of Neuroscience, University of Florida McKnight Brain Institute, Gainesville 32610-0244, USA.
Dube
Michael G
MG
Kalra
Pushpa S
PS
Kalra
Satya P
SP
D002001:Adipose Tissue, Brown / Q000254:growth & development / Q000502:physiology; D000818:Animals; D001066:Appetite / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D002149:Energy Intake; D030762:Estrous Cycle; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D054439:Ghrelin; D006128:Growth / Q000502:physiology; D006946:Hyperinsulinism / Q000503:physiopathology / Q000628:therapy; D007031:Hypothalamus / Q000502:physiology; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood*; D007473:Ion Channels; D020738:Leptin / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D009479:Neuropeptides / Q000235:genetics; D009765:Obesity / Q000503:physiopathology / Q000628:therapy*; D036361:Peptide Hormones / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071256:Uncoupling Protein 1; D014621:Vagina / Q000502:physiology; D015430:Weight Gain / Q000502:physiology
D002352:Carrier Proteins; D054439:Ghrelin; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009479:Neuropeptides; D036361:Peptide Hormones; D012333:RNA, Messenger; D000071256:Uncoupling Protein 1