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Nigrostriatal rAAV-mediated GDNF overexpression induces robust weight loss in a rat model of age-related obesity.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2009 Jun; Vol. 17 (6), pp. 980-91. Date of Electronic Publication: 2009 Mar 10. - Publication Year :
- 2009
-
Abstract
- Intraventricular administration of glial cell line-derived neurotrophic factor (GDNF) in primate and humans to study Parkinson's disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight. In this study, we compared bilateral injections of rAAV2/5-GDNF in hypothalamus versus substantia nigra (SN) in aged Brown-Norway X Fisher 344 rats. Nigrostriatal GDNF overexpression resulted in significantly greater weight loss than rats treated in hypothalamus. The nigral or hypothalamic GDNF-induced weight loss was unrelated to motor activity levels of the rats, though some of the weight loss could be attributed to a transient reduction in food intake. Forebrain DA levels did not account for the observed effects on body weight, although GDNF-induced increases in nucleus accumbens DA may have partially contributed to this effect in the hypothalamic GDNF-treated group. However, only nigrostriatal GDNF overexpression induced activation of phosphorylated extracellular signal-regulated kinase (p-ERK) in a small population of corticotrophin-releasing factor [corticotrophin-releasing hormone (CRH)] neurons located specifically in the medial parvocellullar division (MPD) of the paraventricular nucleus of the hypothalamus. Activation of these hypothalamic CRH neurons likely accounted for the observed metabolic effects leading to weight loss in obese rats.
- Subjects :
- Adiposity genetics
Animals
Blotting, Western
Body Weight genetics
Catecholamines metabolism
Chromatography, High Pressure Liquid
Dependovirus genetics
Dopamine metabolism
Eating genetics
Enzyme-Linked Immunosorbent Assay
Glial Cell Line-Derived Neurotrophic Factor genetics
Glial Cell Line-Derived Neurotrophic Factor metabolism
Hypothalamus metabolism
Immunohistochemistry
Male
Neuropeptide Y metabolism
Obesity metabolism
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Substantia Nigra metabolism
Aging physiology
Glial Cell Line-Derived Neurotrophic Factor physiology
Obesity genetics
Weight Loss genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 17
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 19277011
- Full Text :
- https://doi.org/10.1038/mt.2009.45