The Brown Foundation Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, 77030, USA.
Program of Biochemistry and Cell Biology, The Graduate School of Biomedical Sciences at the University of Texas Health Science Center, Houston, TX, 77030, USA.
Int J Obes (Lond). 2019 Mar;43(3):567-580. doi: 10.1038/s41366-018-0090-5. Epub 2018 May 24.
Nutrient challenge in the form of a high fat (HF) diet causes a reversible reprogramming of the hepatic circadian clock. This depends in part on changes in the recruitment of the circadian transcription factor BMAL1 to genome targets, though the causes and extent of disruption to hepatic and extra-hepatic BMAL1 are unknown. The objective of the study was to determine whether HF diet-induced alterations in BMAL1 function occur across insulin-resistant tissues and whether this could be reversed by restoring whole body insulin sensitivity.
BMAL1 subcellular localization and target recruitment was analyzed in several metabolically active peripheral tissues, including liver, muscle, and adipose tissue under conditions of diet-induced obesity. Animals made obese with HF diet were subsequently treated with rosiglitazone to determine whether resensitizing insulin-resistant tissues to insulin restored hepatic and extra-hepatic BMAL1 function.
These data reveal that both hepatic and extra-hepatic BMAL1 activity are altered under conditions of obesity and insulin resistance. Restoring whole body insulin sensitivity by treatment with the antidiabetic drug rosiglitazone is sufficient to restore changes in HF diet-induced BMAL1 recruitment and activity in several tissues.
This study reveals that a key mechanism by which HF diet interferes with clock function in peripheral tissues is via the development of insulin resistance.
高脂肪（HF）饮食形式的营养挑战会导致肝脏生物钟发生可逆重编程。这部分依赖于昼夜节律转录因子 BMAL1 向基因组靶标的募集变化，尽管尚不清楚肝脏和肝脏外 BMAL1 的破坏原因和程度。本研究的目的是确定 HF 饮食诱导的 BMAL1 功能改变是否发生在胰岛素抵抗组织中，以及通过恢复全身胰岛素敏感性是否可以逆转这种改变。
在几种代谢活跃的外周组织中，包括肝脏、肌肉和脂肪组织中，分析了 BMAL1 的亚细胞定位和靶标募集情况，这些组织在饮食诱导肥胖的情况下。用 HF 饮食使动物肥胖，然后用罗格列酮治疗，以确定使胰岛素抵抗组织对胰岛素重新敏感是否恢复了肝脏和肝脏外 BMAL1 的功能。
这些数据表明，肥胖和胰岛素抵抗条件下，肝脏和肝脏外 BMAL1 活性均发生改变。用抗糖尿病药物罗格列酮治疗恢复全身胰岛素敏感性足以恢复 HF 饮食诱导的 BMAL1 募集和几种组织中活性的改变。
本研究揭示了 HF 饮食通过胰岛素抵抗的发展干扰外周组织时钟功能的一个关键机制。
