Chronic mild stress alters circadian expressions of molecular clock genes in the liver

Kei Takahashi, Tetsuya Yamada, Sohei Tsukita, Keizo Kaneko, Yuta Shirai, Yuichiro Munakata, Yasushi Ishigaki, Junta Imai, Kenji Uno, Yutaka Hasegawa, Shojiro Sawada, Yoshitomo Oka, Hideki Katagiri

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/ lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating over activation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) a, Ppary-1, Ppary-coactivator-1a, and phosphoenolepyruvate carboxy-kinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolism-related genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis over activation. This mechanism might contribute to metabolic disorders in stressful modern societies.

Original languageEnglish
Pages (from-to)E301-E309
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number3
Publication statusPublished - 2013 Feb 1


  • Hypothalamus-pituitary-adrenal axis
  • Liver clock
  • Metabolic disorders
  • Stress

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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