Central leptin gene therapy blocks high-fat diet-induced weight gain, hyperleptinemia, and hyperinsulinemia: increase in serum ghrelin levels.
Recombinant adeno-associated virus (rAAV), encoding either rat leptin (rAAV-lep) or green fluorescent protein (rAAV-GFP, control), was injected intracerebroventricularly in rats consuming a high-fat diet (HFD; 45 kcal%). Caloric consumption and body weight were monitored weekly until the rats were killed at 9 weeks. Untreated control rats consuming regular rat diet (RCD; 11 kcal%) were monitored in parallel. Body weight gain was accelerated in rAAV-GFP + HFD control rats relative to those consuming RCD, despite equivalent kcal consumption. At 9 weeks, serum leptin, free fatty acids, triglycerides, and insulin were elevated in HFD control rats. In contrast, rAAV-lep treatment reduced intake and blocked the HFD-induced increase in weight, adiposity, and metabolic variables. Blood glucose was slightly reduced but within the normal range, and serum ghrelin levels were significantly elevated in rAAV-lep + HFD rats. Uncoupling protein-1 (UCP1) mRNA in brown adipose tissue (BAT), an index of energy expenditure through nonshivering thermogenesis, was decreased in rats consuming HFD. Treatment with rAAV-lep significantly augmented BAT UCP1 mRNA expression, indicating increased thermogenic energy expenditure. These findings demonstrate that central leptin gene therapy efficiently prevents weight gain, increased adiposity, and hyperinsulinemia in rats consuming an HFD by decreasing energy intake and increasing thermogenic energy expenditure.
Dube
Michael G
MG
Department of Physiology and Functional Genomics, University of Florida McKnight Brain Institute, College of Medicine, Gainesville, Florida 32610-0244, USA.
Beretta
Elena
E
Dhillon
Harveen
H
Ueno
Naohiko
N
Kalra
Pushpa S
PS
Kalra
Satya P
SP
D000273:Adipose Tissue; D002001:Adipose Tissue, Brown / Q000737:chemistry; D000818:Animals; D001823:Body Composition; D002352:Carrier Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage*; D002149:Energy Intake; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D054439:Ghrelin; D049452:Green Fluorescent Proteins; D006946:Hyperinsulinism / Q000517:prevention & control*; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins; D009765:Obesity / Q000517:prevention & control; D036361:Peptide Hormones; D010455:Peptides / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D022722:Thermogenesis; D014280:Triglycerides / Q000097:blood; D000071256:Uncoupling Protein 1; D015430:Weight Gain
D002352:Carrier Proteins; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D054439:Ghrelin; D007473:Ion Channels; D020738:Leptin; D008164:Luminescent Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D036361:Peptide Hormones; D010455:Peptides; D012333:RNA, Messenger; D014280:Triglycerides; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D049452:Green Fluorescent Proteins