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 diseases^{2, 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.