Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1937577
- author
- 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
- organization
- publishing date
- 2011
- 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
- pmid:21459327
- 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
- 2016-04-04 07:20:25
- date last changed
- 2024-02-10 19:37:16
@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}}, doi = {{10.1016/j.cmet.2011.02.013}}, volume = {{13}}, year = {{2011}}, }