IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model
(2022) In iScience 25(2). p.1-16- Abstract
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only... (More)
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.
(Less)
- author
- Soylu-Kucharz, Rana LU ; Khoshnan, Ali and Petersén, Åsa LU
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- iScience
- volume
- 25
- issue
- 2
- article number
- 103771
- pages
- 1 - 16
- publisher
- Elsevier
- external identifiers
-
- pmid:35146388
- scopus:85123690679
- ISSN
- 2589-0042
- DOI
- 10.1016/j.isci.2022.103771
- language
- English
- LU publication?
- yes
- additional info
- © 2022 The Author(s).
- id
- 82193556-95d6-4520-bd92-daa3a098a908
- date added to LUP
- 2022-02-15 09:31:30
- date last changed
- 2024-06-27 12:07:51
@article{82193556-95d6-4520-bd92-daa3a098a908,
abstract = {{<p>Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.</p>}},
author = {{Soylu-Kucharz, Rana and Khoshnan, Ali and Petersén, Åsa}},
issn = {{2589-0042}},
language = {{eng}},
number = {{2}},
pages = {{1--16}},
publisher = {{Elsevier}},
series = {{iScience}},
title = {{IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model}},
url = {{http://dx.doi.org/10.1016/j.isci.2022.103771}},
doi = {{10.1016/j.isci.2022.103771}},
volume = {{25}},
year = {{2022}},
}