Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

Brendan Gabriel, Ali Altıntaş, Jonathon A. B. Smith, Laura Sardon-Puig, Xiping Zhang, Astrid L. Basse, Rhianna C. Laker, Hui Gao, Zhengye Liu, Lucile Dollet, Jonas T. Treebak, Antonio Zorzano, Zhiguang Huo, Mikael Rydén, Johanna T. Lanner, Karyn A. Esser, Romain Barrès, Nicolas J. Pillon, Anna Krook, Juleen R. Zierath* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms 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 ARNTL, CLOCK, CRY1 and NR1D1 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. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.
Original languageEnglish
Article numbereabi9654
Number of pages19
JournalScience Advances
Volume7
Issue number43
Early online date20 Oct 2021
DOIs
Publication statusPublished - 22 Oct 2021

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