**3. The nutritional stimuli and circadian rhythms**

Metabolic homeostasis is modulated by circadian rhythms, as mentioned above, but nutritional stimuli affect circadian rhythms and vice versa.

Importantly, the circadian rhythm found in gene expression is tissue-specific, and the type and number of oscillating genes differ depending on the type of tissue or cell [20]. Transcriptional factors can define tissue specificities and result in the diversity of chromatin structures, but an oscillation has been reported to be reconstructed by various nutritional stimuli [6, 21–23]. Notably, the molecular mechanism by which metabolic alterations affect circadian rhythms has been investigated intensively. For example, the transcriptional factors SREBP1 and PPARs, which are related to lipid metabolism, are activated periodically by the intake of a high-fat diet, thereby driving the specific oscillation of gene expression [24, 25]. It has also been shown that fluctuations in energy metabolites are deeply involved in transcriptional regulation. Acetyl-CoA is used as an acetylating substrate for histones and clock genes, and NAD modulates the oscillation of gene expression by acting as a coenzyme for sirtuins that deacetylate proteins [26, 27]. The acetylation of histones is also conducted by S-adenosylmethionine (SAM) by the transfer of a methyl donor from SAM. S-adenosylhomocysteine (SAH) is produced from SAM by methyltransferases. Interestingly, the SAH hydrolyzing enzyme binds to clock genes and contributes to the interaction among methionine metabolism, clock gene expression, and chromatin remodeling [28]. These findings indicate the adaptability and plasticity of transcriptional regulation of clock genes, which flexibly respond to metabolic changes, and imply the existence of a circuit in which transcriptional and metabolic rhythms regulate each other.

The impact of the timing of the nutritional stimuli has also been investigated. The exposure of the intestine to the nutrients is fundamental, but bile acids in the intestine secreted from the liver are also reported to be important regulators to elicit circadian rhythms [29]. Importantly, time-restricted feeding (TRF), which limits feeding time, has been reported to be a good method for restoring circadian rhythms by modulating nutritional stimuli. Even when the food had the same amount of energy in this model, if the feeding time was limited to less than nine hours a day (TRF) in comparison with the mice fed ad libitum for 24 h, the suppression of body fat accumulation and

#### **Figure 1.**

*The interaction between the circadian rhythm in the central nervous system (CNS), peripheral organs, and sleep. The central clock in the hypothalamus is the master keeper of circadian rhythm and is primarily entrained by light and dark stimuli, while feeding-fasting rhythm, that is, nutritional stimuli, entrains peripheral clocks in peripheral organs such as the liver and intestine. Sleep rhythm is evoked mainly by the central clock, and disturbed sleep affects the circadian rhythm in the CNS. The rhythm in peripheral organs that is regulated by nutritional stimuli may modulate sleep rhythm.*

the improvement of glucose intolerance were observed [30, 31]. In addition, TRF improved the metabolic disarrangement found in various organs, and the circadian rhythm of intestinal bacteria and functions recovered. These findings indicate that nutritional stimuli. That is, diet is an important regulator of circadian rhythm and systemic metabolism (**Figure 1**).
