Gabriel Brendan M, Altıntaş 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 Antonio, Huo Zhiguang, Rydén Mikael, Lanner Johanna T, Esser Karyn A, Barrès Romain, Pillon Nicolas J, Krook Anna, Zierath Juleen R
Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Aberdeen Cardiovascular and Diabetes Centre, The Rowett Institute, University of Aberdeen, Aberdeen, UK.
Sci Adv. 2021 Oct 22;7(43):eabi9654. doi: 10.1126/sciadv.abi9654. Epub 2021 Oct 20.
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 , and 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.
昼夜节律由转录激活因子和抑制因子的自动调节反馈回路产生。昼夜节律紊乱会导致2型糖尿病（T2D）的发病机制。我们阐明了时钟基因昼夜节律的改变是否与T2D中的代谢功能障碍有关。核心时钟基因、的转录循环在T2D患者的骨骼肌中发生改变，这与循环基因数量和振幅的减少以及昼夜氧消耗紊乱有关。与线粒体内相关的基因在正常糖耐量而非T2D中富集有节律性峰值，并且与胰岛素敏感性呈正相关。染色质免疫沉淀测序确定了CLOCK和BMAL1与与胰岛素敏感性相关的线粒体内基因结合，这意味着核心时钟的调节作用。线粒体内破坏改变了核心时钟基因表达和自由基产生，白藜芦醇治疗可恢复这些现象。我们确定了线粒体功能与节律性基因表达之间的双向通信，这些过程在糖尿病中受到干扰。
