Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus

Mol Ther. 2001 Aug;4(2):139-45. doi: 10.1006/mthe.2001.0427.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agouti-Related Protein
  • Animals
  • Appetite*
  • Body Weight*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Female
  • Genetic Therapy*
  • Genetic Vectors
  • Hypothalamus / cytology
  • Hypothalamus / drug effects
  • Hypothalamus / physiology*
  • In Situ Hybridization
  • Insulin / blood
  • Intercellular Signaling Peptides and Proteins
  • Ion Channels
  • Leptin / blood
  • Leptin / genetics*
  • Leptin / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mitochondrial Proteins
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Plasmids
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Uncoupling Protein 1

Substances

  • Agouti-Related Protein
  • Carrier Proteins
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Ion Channels
  • Leptin
  • Membrane Proteins
  • Mitochondrial Proteins
  • Neuropeptide Y
  • Proteins
  • Ucp1 protein, rat
  • Uncoupling Protein 1
  • Pro-Opiomelanocortin