**1. Introduction**

The term circadian rhythm refers to the natural and internal process that regulates the sleep-wake cycle in all mammals, and repeats about every 24 h, which is almost the same as the rotation of the earth. Circadian rhythm is not only an important mechanism for the sleep-wake cycle, but also for the homeostasis of endocrine and metabolic systems that rely on the body to predict and adapts to changing environments during daytime and nighttime. Since the circadian rhythm is maintained even in the absence of light stimulation, this rhythm is called the "circadian clock" and determines diurnal fluctuations such as blood pressure and body temperature [1]. In mammals, the suprachiasmatic nucleus (SCN) in the hypothalamus of the brain is the master keeper of circadian rhythms, and it also controls the circadian rhythms of other organs. Animals in which the SCN has been damaged are unable to perform circadian activities, and the transplantation of the SCN restores their circadian rhythm. SCN neurons form a network and transmit circadian rhythms by transcription factors CLOCK, BMAL1, and Period (Per) and Cryptochrome (CRY), which suppress their activities.

Although the circadian clock is best known for producing 24-h cycle rhythms in movements, metabolism, and hormones, a circadian rhythm also exists in peripheral organs, including the liver and digestive tract. These rhythms are called peripheral clocks. In addition to the rhythms of clock genes in peripheral organs, nutritional stimuli, such as diet, have also been shown to modulate circadian rhythms in peripheral organs. Furthermore, the circadian rhythms in peripheral organs likely affect the central clocks and *vice versa*.

In this chapter, we will focus on the role that circadian rhythms play in systemic metabolism as well as the role that nutritional stimuli play in circadian rhythm and sleep.

#### **2. The circadian rhythms and metabolic regulation**

Circadian rhythms can be found in humans, including a sleep-wake rhythm, an eating-hunger rhythm, and hormonal fluctuations that occur on a roughly 24-h cycle that is synchronized with the light-dark cycle [2]. This rhythm is mainly driven by the biological clock, which in mammals consists of a central clock located in the hypothalamus and a peripheral clock in other organs. Light is the main environmental synchronizer of the central clock, while eating and motion synchronize the peripheral clock. Optical signals are transmitted from the central clock to peripheral organs, such as the skin and muscles, and regulate the circadian rhythm of the cell cycle and insulin sensitivity [3].

In mammals, the circadian clock is mainly tuned by transcription factors called Circadian Locomotor Output Cycles Kaput (CLOCK) and brain and muscle ARNTlike protein-1 (BMAL1), which form a heterodimer and activate transcription of target genes in the light phase [4, 5]. They target genes that suppress biological clocks such as Per (Period) and Cry (Cryptochrome), which suppress the transcription of CLOCK-BMAL1 in the dark phase [5]. The clock gene circuit is also regulated by the nuclear receptors retinoic acid receptor-related orphan receptor (ROR) and REV-ERB, which regulate Bmal1 gene expression positively and negatively, respectively. In addition to the transcriptional feedback loop of clock genes, various oscillations of gene expression are modulated by the regulation of transcription factors other than clock genes [6].

Circadian rhythms in the expression of genes and proteins have also been observed in peripheral organs such as the liver and intestine. In fact, approximately 30% of gene expression in the intestinal tract shows a circadian rhythm, and this is also observed in the proliferation of intestinal epithelium and intestinal permeability. A circadian rhythm can also be observed in the blood concentration of triglyceride-rich lipoproteins synthesized in the intestinal tract [7, 8]. Furthermore, clock genes such as Clock and Bmal1 are expressed in the gastrointestinal tract, and their expression is particularly high in the lower gastrointestinal tract and large intestine, with the expression site found mainly in the epithelial layer rather than the mucosal layer [8].

These clock genes affect the functions of the intestine by altering the expression of target genes, such as sodium-glucose cotransporter (SGLT) 1, which is involved in glucose absorption and peptide transporter (PEPT) 1, which is involved in peptide absorption. In mice, the transporter involved in glucose uptake increases in the dark phase, while the peptide transporter increases during the light phase. Similarly, a diurnal variation was observed in lipid absorption, and the number of genes involved in lipid absorption increased in the dark phase. Additionally, it has been reported that in mice with a clock gene mutation, the absorption of sugar, triglyceride, and cholesterol from intestinal contents was higher and the absorption of peptides was lower. In addition to intestinal epithelial cells, enteroendocrine cells, such as ghrelin-producing cells, are also regulated by clock genes such as Bmal1 and Per1/2. For example, in *Bmal1*-deficient mice, no diurnal variation in ghrelin nor diurnal variation in feeding was observed [9, 10]. It has also been reported that a circadian rhythm is observed in the expression of toll-like receptors in the small intestine, which is involved in intestinal immunity [11]. Since diurnal rhythms in the function of the intestine were first observed, it was assumed that they may affect the intestinal microbiota in the intestinal lumen. Recent findings

#### *Circadian Clock, Sleep, and Diet DOI: http://dx.doi.org/10.5772/intechopen.100421*

have revealed that the intestinal microbiota plays a pivotal role in the regulation of host homeostasis [12–16]. Importantly, several groups have reported diurnal oscillations of intestinal microbiota [17–19]. The bacteria belonging to Clostridiales and Lactobacillaceae showed diurnal variation, and at the species level, *Lactobacillus reuteri* decreased and *Dehalobacterium* increased in the dark phase. Along with the diurnal changes in the composition of intestinal bacteria, diurnal fluctuations are also observed in the functions of the microbiota, such as vitamin and nucleic acid metabolism by the bacteria. The functions of DNA repair, cell proliferation, and mucin degradation were dominant in the dark phase, whereas bacterial motility and sensing pathways were dominant in the light phase. The diurnal rhythm in intestinal microbiota was also examined in humans, and it was found that *Parabacteroides* and *Bulleidia* were increased in the daytime and decreased at night, while *Lachnospira* decreased in the daytime and increased in the nighttime. This is consistent with the findings in mice and suggests that there are diurnal rhythms in protein synthesis as it primarily occurs in the daytime.

These findings demonstrate that peripheral organs, including intestinal microbiota, have circadian rhythms and systemically modulate energy homeostasis and metabolism.
