Akihiko Taguchi

Objective: Circadian rhythm disruption is associated with metabolic disorders, yet the role of clock genes in glucose metabolism remains unclear. D‐box binding protein (DBP) is a clock output gene that activates the D‐box, and we used systemic Dbp knockout (KO) mice to investigate DBP's role in glucose metabolism. Methods: We generated two independent KO mouse lines. Intraperitoneal insulin tolerance tests (IPITTs) were performed in 13‐week‐old male mice at zeitgeber time (ZT) 1 and ZT 13. To assess hepatic and muscle insulin sensitivity, we examined 2‐deoxy‐D‐glucose (2DG) content and AKT phosphorylation followed by transcriptome analysis using muscle. Results: In the KO mice, enhanced insulin sensitivity was observed in ZT1 following IPITT compared to wild‐type (WT) mice, but not in ZT13. These findings indicate that while systemic insulin sensitivity fluctuates throughout the day in WT mice, it does not fluctuate in KO mice. Increased glucose uptake and AKT phosphorylation in gastrocnemius muscle (GM), but not the liver, were observed in KO mice at ZT1. Plasma nonesterified fatty acid (NEFA) levels were reduced during the inactive phase in KO mice. Muscle transcriptome analysis identified chemokine and cytokine–related pathways as the most enriched, including C–C motif chemokine ligand 5 (CCL5) and its receptor C–C chemokine receptor type 5 (CCR5). Conclusion: Muscle insulin sensitivity oscillates, with a reduction during the inactive phase. This study demonstrates that DBP deficiency suppresses circadian fluctuations of muscle insulin sensitivity, likely via plasma NEFA and CCL5‐CCR5 signaling. DBP plays a role in circadian regulation of muscle insulin sensitivity.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic intestinal inflammation. Recent research has highlighted the significant interplay between IBD pathogenesis and circadian rhythms. This review synthesizes current evidence regarding circadian regulation in IBD, covering three main areas: (1) circadian rhythms in intestinal physiology, (2) circadian disruption patterns in IBD patients, and (3) the role of clock genes in IBD pathogenesis. We discuss how these findings may inform novel chronotherapeutic approaches for IBD treatment. Future research directions that could facilitate translation of chronobiological insights into clinical applications are also explored.

Rising nicotinamide adenine dinucleotide (NAD+) levels mitigate the onset and progression of age-related diseases including metabolic disorders. Several studies have demonstrated that NAD+ levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake and thereby prevent metabolic disorders. However, the acute effects of NMN administration on metabolism remain unclear. We observed metabolic dynamics after a single bolus injection of NMN. Sirt1 and Nampt mRNA levels were increased in the liver suggesting that intracellular NAD+ increased after injection. During OGTT, glucose tolerance and insulin secretion did not change significantly in response to NMN administration, while during ITT, increased insulin sensitivity was observed in muscle. NMN administration decreased serum non-esterified free fatty acid (NEFA) concentrations, which would presumably be responsible for the increased muscle insulin sensitivity. Furthermore, NMN administration reduced the respiratory quotient, confirming that NMN promotes utilization of lipids as an energy source. Our data demonstrate acute effects of NMN on metabolism and raise the possibility of NMN as a treatment for metabolic disorders.

Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.

Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.