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  Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice.

Meyer-Kovac, J., Kolbe, I., Ehrhardt, L., Leliavski, A., Husse, J. L., Salinas, G., et al. (2017). Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. Molecular Metabolism, 6(6), 512-523. doi:10.1016/j.molmet.2017.03.008.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-B0A0-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-B89F-C
Genre: Journal Article

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 Creators:
Meyer-Kovac, J., Author
Kolbe, I., Author
Ehrhardt, L., Author
Leliavski, A., Author
Husse, J. L.1, Author              
Salinas, G., Author
Lingner, T., Author
Tsang, A. H.2, Author              
Barclay, J. L., Author
Oster, H.2, Author              
Affiliations:
1Department of Genes and Behavior, MPI for biophysical chemistry, Max Planck Society, ou_persistent34              
2Research Group of Circadian Rhythms, MPI for Biophysical Chemistry, Max Planck Society, ou_578594              

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Free keywords: Circadian clock; Clock gene; High-fat diet; Liver; Transcription; Gene therapy
 Abstract: Objective: Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown. Methods: Metabolic parameters of wild-type (WT) and Clock(Delta 19) mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT-Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied. Results: Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock-dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways. Conclusion: Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders. (

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Language(s): eng - English
 Dates: 2017-03-292017-06
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.molmet.2017.03.008
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Title: Molecular Metabolism
Source Genre: Journal
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Pages: - Volume / Issue: 6 (6) Sequence Number: - Start / End Page: 512 - 523 Identifier: -