title: Hypothalamic rAAV-mediated GDNF gene delivery ameliorates age-related obesity.
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.
authors.affiliation: Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, FL 32608-1197, USA. ntumer@ufl.edu
authors.forename: Nihal
authors.initials: N
authors.lastname: Tümer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Scarpace
authors.forename: M Devrim
authors.initials: MD
authors.lastname: Dogan
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Broxson
authors.forename: Michael
authors.initials: M
authors.lastname: Matheny
authors.forename: David M
authors.initials: DM
authors.lastname: Yurek
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Peden
authors.forename: Corinna
authors.initials: C
authors.lastname: Burger
authors.forename: Nicholas
authors.initials: N
authors.lastname: Muzyczka
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Mandel
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000627:therapeutic use*; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor