Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice
| Autor: | Jana Husse, Gabriela Salinas, Johanna L. Barclay, Judit Meyer-Kovac, Anthony H. Tsang, Alexei Leliavski, Thomas Lingner, Lea Ehrhardt, Henrik Oster, Isa Kolbe |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty lcsh:Internal medicine Circadian clock Mutant CLOCK Proteins Hyperphagia Biology Diet High-Fat Transcriptome Mice 03 medical and health sciences Gene therapy Internal medicine medicine Clock gene Animals Obesity Circadian rhythm lcsh:RC31-1245 Molecular Biology 2. Zero hunger Leptin Feeding Behavior Genetic Therapy Cell Biology 3. Good health Mice Inbred C57BL CLOCK High-fat diet 030104 developmental biology Endocrinology Liver Mutation Original Article Ghrelin Transcription |
| Zdroj: | Molecular Metabolism, Vol 6, Iss 6, Pp 512-523 (2017) Molecular Metabolism |
| ISSN: | 2212-8778 |
| Popis: | 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 ClockΔ19 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. Graphical abstract Image 1 Highlights • Normalizing diurnal feeding rhythms does not rescue body weight regulation in Clock mutant mice. • Gene therapy restores liver clock function in Clock mutant mice. • Liver clock rescue improves metabolic homeostasis under high-fat diet conditions. |
| Databáze: | OpenAIRE |
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