Hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related obesity

Nihal Tümer, Philip J. Scarpace, M. Devrim Dogan, Christopher S. Broxson, Michael Matheny, David M. Yurek, Carmen S. Peden, Corinna Burger, Nicholas Muzyczka, Ronald J. Mandel

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Intraventricular delivery of glial cell line-derived neurotrophic factor (GDNF) results in weight loss. We hypothesized that this effect of GDNF was likely mediated via its effects on dopaminergic neurons in the hypothalamus. Continuous rAAV-mediated GDNF expression in the hypothalamus of young and senescent rats resulted in weight loss compared to controls. However, GDNF-induced weight loss was unrelated to alterations in hypothalamic dopamine levels. The weight loss was associated with decreased food intake and increased energy expenditure, but these effects were not mediated by changes in hypothalamic NPY or POMC expression. Moreover, uncoupling protein 1 levels were unchanged in brown adipose tissue (BAT). The reduction in weight and adiposity were as great or greater in the aged rats even though aged rats are generally resistant to weight loss therapies. In summary, central GDNF gene delivery reduces weight and adiposity in young and aged rats through decreased food intake and increased energy expenditure. Our observations in aged rats suggest that GDNF may be especially effective in reducing obesity in aged obese rats.

Original languageEnglish
Pages (from-to)459-470
Number of pages12
JournalNeurobiology of Aging
Volume27
Issue number3
DOIs
StatePublished - Mar 2006

Bibliographical note

Funding Information:
This study was supported by the Medical Research Service of the Department of Veterans Affairs and NIH P01 NS 36302. The authors would like to thank Izzie Williams for expert histological assistance. Nicholas Muzyczka is an inventor on patents related to recombinant AAV Technology and owns equity in a gene therapy company that is commercialising AAV for gene therapy applications.

Keywords

  • Aging
  • GDNF
  • Gene delivery
  • Hypothalamus
  • Obesity

ASJC Scopus subject areas

  • Neuroscience (all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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