输出时钟基因在调节葡萄糖代谢中的作用。

IF 3.1 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Akihiko Taguchi, Yasuharu Ohta, Yuko Nagao, Yukio Tanizawa
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引用次数: 0

摘要

昼夜节律是导致24小时昼夜循环的生理活动的内源性自主振荡器。这种节律被认为是一种调节生物体的系统,允许它们在昼夜循环中进行有效的生物活动。人类的昼夜节律设定在24小时11±16分钟,比白天的昼夜节律(24小时)稍长。因此,当生活在黑暗的房间里时,每天醒来的时间会稍微延迟1。电灯的发明彻底改变了社会,人类现在可以在晚上工作,包括轮班工作,据报道,这种昼夜节律的破坏增加了胰岛素抵抗,也增加了2型糖尿病和心血管疾病的风险。在人类中,昼夜节律的中心位于视交叉上核,节律是由一组被称为时钟基因的基因产生的。产生昼夜节律的分子机制如下:首先,一组核心时钟基因产物clock - bmal1的异二聚体与Per和Cry时钟基因的启动子结合,从而激活Per和Cry的转录。翻译后的PER和CRY通过负反馈机制抑制clock - bmal1的转录活性,该循环每24小时循环一次,产生昼夜节律(图1)。参与该回路的基因被称为“核心时钟基因”。核心时钟基因,如Bmal1和clock,通过调节一组具有E-box序列的基因来产生昼夜节律,这些基因提供了细胞功能的节律。例如,在胰岛β细胞中,BMAL1和CLOCK直接调节一组与胰岛素分泌相关的基因,产生胰岛素分泌的独特昼夜节律4。除了这些直接调控因子外,还有一组转录因子,称为时钟输出基因,将核心时钟基因的信号传递给下游效应基因。时钟输出基因包括DBP、TEF、HLF和E4BP4。我们和其他人最近对它们对代谢的影响进行了严格的研究(表1)。在这里,我们讨论了这些时钟输出基因的作用,重点是葡萄糖代谢。未来的研究有望揭示外周时钟基因调控的机制,为开发靶向这些基因的药物开辟道路,同时不破坏中心昼夜节律。虽然影响核心生物钟基因的药物在小鼠中显示出代谢益处,但它们在代谢性疾病患者中的应用需要进一步研究,以尽量减少对中枢生物钟的任何不利影响。Yukio Tanizawa是《糖尿病调查杂志》的编辑委员会成员,也是本文的合著者。为了尽量减少偏倚,他被排除在所有与接受这篇文章发表相关的编辑决策之外。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The roles of output clock genes in regulating glucose metabolism

The roles of output clock genes in regulating glucose metabolism

Circadian rhythm is an endogenous autonomous oscillator of physiological activities resulting in 24 h day/night cycles. This rhythm is regarded as a system regulating organisms allowing them to carry out efficient biological activities during the day–night cycle. In humans, the rhythm is set at 24 h and 11 ± 16 min, which is slightly longer than the day rhythm (24 h). Therefore, when living in a dark room, the waking time is slightly delayed each day1.

The invention of electric light revolutionized society, with humans now able to work at night, including shift work, and such disruption of the circadian rhythm reportedly increases insulin resistance, as well as raising the risks of type 2 diabetes and cardiovascular diseases2, 3.

In humans, the center of the circadian rhythm is located in the suprachiasmatic nucleus, and the rhythm is generated by a set of genes known as clock genes. The following molecular mechanism generates circadian rhythms: first, the heterodimer of CLOCK-BMAL1, a set of the core clock gene products, binds to the promoters of the Per and Cry clock genes, thereby activating both Per and Cry transcription. The translated PER and CRY then suppress CLOCK-BMAL1 transcriptional activity through a negative feedback mechanism, and this loop cycles once every 24 h to generate a circadian rhythm (Figure 1). The genes involved in this circuit are referred to as ‘core clock genes’.

Core clock genes such as Bmal1 and Clock generate circadian rhythms by regulating a group of genes with E-box sequences that provide a rhythm underlying cellular functions. For example, in pancreatic islet β-cells, BMAL1 and CLOCK directly regulate a group of genes related to insulin secretion, generating a distinct circadian rhythm for insulin secretion4. In addition to these direct regulatory factors, another set of transcription factors, referred to as clock output genes, transmit the signals from core clock genes to downstream effector genes. Clock output genes include DBP, TEF, HLF, and E4BP4. We and others have recently conducted rigorous studies of their effects on metabolism (Table 1). Herein, we discuss the roles of these clock output genes, focusing on glucose metabolism.

Future research is anticipated to reveal the mechanisms underlying peripheral clock gene regulation, opening the way to the development of drugs targeting these genes without disrupting the central circadian rhythm. While drugs influencing core clock genes have shown metabolic benefits in mice, their use in patients with metabolic diseases requires further investigation aimed at minimizing any adverse effects on the central biological clock.

Yukio Tanizawa is an Editorial Board member of Journal of Diabetes Investigation and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.

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来源期刊
Journal of Diabetes Investigation
Journal of Diabetes Investigation ENDOCRINOLOGY & METABOLISM-
CiteScore
6.50
自引率
9.40%
发文量
218
审稿时长
6-12 weeks
期刊介绍: Journal of Diabetes Investigation is your core diabetes journal from Asia; the official journal of the Asian Association for the Study of Diabetes (AASD). The journal publishes original research, country reports, commentaries, reviews, mini-reviews, case reports, letters, as well as editorials and news. Embracing clinical and experimental research in diabetes and related areas, the Journal of Diabetes Investigation includes aspects of prevention, treatment, as well as molecular aspects and pathophysiology. Translational research focused on the exchange of ideas between clinicians and researchers is also welcome. Journal of Diabetes Investigation is indexed by Science Citation Index Expanded (SCIE).
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