title: Chronic mild stress alters circadian expressions of molecular clock genes in the liver.
abstract: 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 overactivation 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) α, Pparγ-1, Pparγ-coactivator-1α, and phosphoenolepyruvate carboxykinase, 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 overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies.
authors.affiliation: Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Sohei
authors.initials: S
authors.lastname: Tsukita
authors.forename: Keizo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shirai
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Munakata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Shojiro
authors.initials: S
authors.lastname: Sawada
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism*; D057906:Circadian Clocks / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D056926:CLOCK Proteins