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Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.

Hult Lundh, Sofia LU ; Soylu, Rana LU ; Björklund, Tomas LU ; Belgardt, Bengt F; Mauer, Jan; Brüning, Jens C; Kirik, Deniz LU and Petersén, Åsa LU (2011) In Cell Metabolism 13(4). p.428-439
Abstract
In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic... (More)
In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Metabolism
volume
13
issue
4
pages
428 - 439
publisher
Cell Press
external identifiers
  • wos:000289381300013
  • pmid:21459327
  • scopus:79953756679
ISSN
1550-4131
DOI
10.1016/j.cmet.2011.02.013
language
English
LU publication?
yes
id
74430580-ef8f-4d2e-812d-b92eac363084 (old id 1937577)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21459327?dopt=Abstract
date added to LUP
2011-05-02 09:58:03
date last changed
2017-10-22 04:51:44
@article{74430580-ef8f-4d2e-812d-b92eac363084,
  abstract     = {In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.},
  author       = {Hult Lundh, Sofia and Soylu, Rana and Björklund, Tomas and Belgardt, Bengt F and Mauer, Jan and Brüning, Jens C and Kirik, Deniz and Petersén, Åsa},
  issn         = {1550-4131},
  language     = {eng},
  number       = {4},
  pages        = {428--439},
  publisher    = {Cell Press},
  series       = {Cell Metabolism},
  title        = {Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.},
  url          = {http://dx.doi.org/10.1016/j.cmet.2011.02.013},
  volume       = {13},
  year         = {2011},
}