Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle.
Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle.
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DOI：
10.1126/sciadv.abi9654
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发表时间：
2021-10-22
期刊：
影响因子：
13.6
通讯作者：
Zierath JR
中科院分区：
文献类型：
--
作者：
Gabriel BM;Altıntaş A;Smith JAB;Sardon-Puig L;Zhang X;Basse AL;Laker RC;Gao H;Liu Z;Dollet L;Treebak JT;Zorzano A;Huo Z;Rydén M;Lanner JT;Esser KA;Barrès R;Pillon NJ;Krook A;Zierath JR
线粒体活动的日常节律紊乱可能导致2型糖尿病骨骼肌胰岛素抵抗。昼夜节律是由转录激活因子和抑制因子的自动调节反馈环产生的。昼夜节律破坏有助于2型糖尿病（T2D）的发病机制。我们阐明了生物钟基因的昼夜节律改变是否与T2D的代谢功能障碍有关。核心时钟基因BMAL1，CLOCK和PER3的转录周期在T2D个体的骨骼肌中发生了改变，这与循环基因的数量和幅度减少以及昼夜氧消耗紊乱有关。在正常葡萄糖耐量中，内分泌相关基因富含节律性峰值，但T2D不存在，并且与胰岛素敏感性呈正相关。染色质免疫沉淀测序鉴定了CLOCK和BMAL1与胰岛素敏感性相关的线粒体内基因的结合，涉及核心时钟的调节。线粒体内部的破坏改变了核心时钟基因的表达和自由基的产生，这种现象可以通过白藜芦醇治疗恢复。我们确定了线粒体功能和节律性基因表达之间的双向通信，这是糖尿病中受到干扰的过程。
Disturbances in daily rhythms of mitochondrial activity may contribute to skeletal muscle insulin resistance in type 2 diabetes. 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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影响因子：
8.1
作者：
Dyar KA;Ciciliot S;Wright LE;Biensø RS;Tagliazucchi GM;Patel VR;Forcato M;Paz MI;Gudiksen A;Solagna F;Albiero M;Moretti I;Eckel-Mahan KL;Baldi P;Sassone-Corsi P;Rizzuto R;Bicciato S;Pilegaard H;Blaauw B;Schiaffino S
通讯作者：
Schiaffino S
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
3.5
作者：
de Goede P;Wefers J;Brombacher EC;Schrauwen P;Kalsbeek A
通讯作者：
Kalsbeek A
影响因子：
6.3
作者：
Andersson, Daniel P.;Thorell, Anders;Hoffstedt, Johan
通讯作者：
Hoffstedt, Johan
影响因子：
64.5
作者：
Balsalobre, A;Damiola, F;Schibler, U
通讯作者：
Schibler, U