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IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington's disease mouse model

Soylu-Kucharz, Rana and Khoshnan, Ali and Petersen, Åsa (2021) IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington's disease mouse model. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210409-154052881

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Abstract

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, and underlying mechanisms are not fully known. As the IKKβ/NF-kB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-kB in hypothalamus-specific HD metabolic changes. Methods: Using viral vectors, we expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) fragments in the hypothalamus of mice without IKKβ in the CNS (IKKβ^(-/-)) and control mice (IKKβ^(+/+)). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Results: 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. Conclusions: The expression of mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.04.08.438894DOIDiscussion Paper
ORCID:
AuthorORCID
Soylu-Kucharz, Rana0000-0002-7872-5322
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted April 9, 2021. This work was supported by grants from the Swedish Medical Research Council (grant numbers 2013/03537 and 2018/02559), the Province of Skåne State Grants (ALF) as well as the Knut and Alice Wallenberg Foundation (# 2019.0467) to ÅP. ÅP is a Wallenberg Clinical Scholar (Knut and Alice Wallenberg Foundation # 2019.0467). RSK was supported by Svenska Sällskapet för Medicinsk Forskning fellowship. We are grateful for the excellent technical assistance provided by Björn Anzelius, Anneli Josefsson, Ulla Samuelsson and Ulrika Sparrhult-Bjork at Lund University. Author contributions statements: RS, ÅP, and AK conceived and designed the experiments. RSK performed the experiments. RSK and ÅP analyzed the data. RSK and ÅP wrote the first draft of the manuscript. All authors were involved in editing the manuscript and approved the final version. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
Swedish Medical Research Council2013/03537
Swedish Medical Research Council2018/02559
Province of Skåne StateUNSPECIFIED
Knut and Alice Wallenberg Foundation2019.0467
Svenska Sällskapet för Medicinsk ForskningUNSPECIFIED
Subject Keywords:Huntington's disease, IKKβ pathway, metabolism, hypothalamus, obesity
Record Number:CaltechAUTHORS:20210409-154052881
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210409-154052881
Official Citation:IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington's disease mouse model. Rana Soylu Kucharz, Ali Khoshnan, Asa Petersen. bioRxiv 2021.04.08.438894; doi: https://doi.org/10.1101/2021.04.08.438894.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108683
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Apr 2021 01:27
Last Modified:19 Apr 2021 21:58

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