Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Circadian rhythms are generated by an autoregulatory feedback loop of transcriptional activators and repressors. Circadian rhythm disruption contributes to type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction...

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Bibliographic Details
Authors: Gabriel, Brendan M., Altintas, Ali, Smith, Jonathon A. B., Sardon-Puig, Laura, Zhang, Xiping, Basse, Astrid L., Laker, Rhianna C., Gao, Hui, Liu, Zhengye, Dollet, Lucile, Treebak, Jonas T., Zorzano Olarte, Antonio, Huo, Zhiguang, Rydén, Mikael, Lanner, Johanna T., Esser, Karyn A., Barrès, Romain, Pillon, Nicolas J., Krook, Anna, Zierath, Juleen R.
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/187166
Online Access:https://hdl.handle.net/2445/187166
Access Level:Open access
Keyword:Ritmes circadiaris
Diabetis
Circadian rhythms
Diabetes
Description
Summary:Circadian rhythms are generated by an autoregulatory feedback loop of transcriptional activators and repressors. Circadian rhythm disruption contributes to type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core-clock genes BMAL1, CLOCK, and PER3 was altered in skeletal muscle from individuals with T2D, and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Inner mitochondria-associated genes were enriched for rhythmic peaks in normal glucose tolerance, but not T2D, and positively correlated with insulin sensitivity. Chromatin immunoprecipitation sequencing identified CLOCK and BMAL1 binding to inner-mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Inner-mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bidirectional communication between mitochondrial function and rhythmic gene expression, processes that are disturbed in diabetes.

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