Role of clock genes in insulin secretion

Abstract

Molecular mechanism of circadian rhythm.

Circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator‐like protein 1 (BMAL1) are master clock genes that regulate circadian rhythm in the hypothalamus and peripheral tissues in mammals; and control not only sleep cycle, but also many other physiological functions, such as body temperature, heart rate and hormone secretion. CLOCK and BMAL1 protein form a heterodimer and bind to enhancer box (E‐box) elements located upstream of circadian rhythm‐related genes, which are period (PER) and cryptochrome (CRY), and non‐circadian rhythm‐related genes, resulting in production of PER, CRY and other non‐circadian rhythm‐related proteins. In the cytoplasm, PER and CRY protein form a heterodimer that is subsequently translocated into the nucleus and inhibits CLOCK and BMAL1‐induced transcriptions. This negative feedback loop is an important part of mammalian circadian rhythm (Figure 1)1.

Figure 1.

Molecular mechanism of circadian rhythm. Circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator‐like protein 1 (BMAL1) protein form a heterodimer and bind to E‐box elements, resulting in induction of period (PER), cryptochrome (CRY) and non‐circadian rhythm‐related gene transcriptions. In the cytoplasm, PER and CRY protein is subsequently translocated into the nucleus, and inhibits CLOCK and BMAL1‐induced transcriptions (negative feedback). E‐box, enhancer box.

Recent studies of CLOCK‐mutant and BMAL‐knockout mice show that circadian rhythm influences the development of metabolic syndrome. Locomotor activity of CLOCK‐mutant mice was higher than that of wild‐type mice in the light phase condition, and the feeding pattern of the mutant mice was apparently different from that of wild‐type mice2. Energy expenditure was decreased and bodyweight was increased in the mutant mice compared with that in wild‐type mice. Furthermore, plasma triglyceride and low‐density lipoprotein cholesterol concentrations were decreased in mutant mice. In contrast, bodyweight and adipose tissue size were significantly decreased in systemic BMAL1‐knockout mice compared with wild‐type mice.3 BMAL1‐knockout mice had higher plasma triglyceride and low‐density lipoprotein cholesterol concentrations compared with wild‐type mice. These results show that CLOCK and BMAL1 are involved in lipid metabolism and bodyweight control. However, there was a large difference in phenotype between CLOCK‐mutant and BMAL‐knockout mice. It is speculated that CLOCK and BMAL1 regulates different non‐circadian proteins, which are associated with lipid metabolism and obesity.

Previously, β‐cell‐specific BMAL1‐knockout mice were generated to evaluate the effect of BMAL1 on insulin secretion4. Plasma insulin concentrations after intraperitoneal glucose injection were significantly lower in β‐cell‐specific BMAL1‐knockout mice compared with those in wild‐type mice, resulting in hyperglycemia. Insulin secretion in response to glucose, adenylyl cyclase activator (forslolin), glucagon‐like peptide‐1 receptor agonist (exendin‐4), cyclic adenosine 3′, 5′‐monophosphate (8‐bromo‐cyclic adenosine 3′, 5′‐monophosphate) and hyperdepolarization (KCl) were significantly decreased in the isolated islets of β‐cell‐specific BMAL1‐knockout mice compared with wild‐type mice. These results show that BMAL1 is also involved in insulin secretion. However, the detailed mechanism of BMAL1‐mediated regulation of insulin secretion from pancreatic β‐cells is unclear. Perelis et al.5 clearly showed the regulatory role of BMAL1 in insulin secretion by genome‐wide analysis of isolated islets. They generated tamoxifen‐induced β‐cell‐specific BMAL1‐knockout mice, and showed that acquired BMAL1 deficiency in β‐cells decreases insulin secretion in response to glucose, forskolin, 8‐bromo‐cyclic adenosine 3′, 5′‐monophosphate and KCl. Genomic‐wide analysis using ribonucleic acid sequence suggested reduction of not only circadian rhythm‐related genes, but also genes associated with transport and membrane fusion of insulin vesicle in the islets. Additionally, data of chromatin immunoprecipitation‐sequence showed that CLOCK and BMAL1 bind at distal regulatory sites of circadian rhythm‐related genes in β‐cells. This region also contained the active enhancer at which pancreatic transcriptional factor pancreatic and duodenal homeobox 1 bind. Thus, clock genes regulate the genes (Pdx1) that are associated with insulin secretion and production in β‐cells.

Disclosure

The authors declare no conflict of interest.