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

Dec 6, 2012American journal of physiology. Endocrinology and metabolism

Long-term mild stress changes daily patterns of internal clock genes in the liver

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Abstract

Chronic mild stress in BALB/c mice elevated serum corticosterone levels and phase-shifted circadian gene expressions in the liver.

The chronic mild stress procedure overactivated the HPA axis, indicated by increased serum corticosterone.
Altered rhythmic expressions of core clock genes in the liver were observed, while those in the hypothalamic suprachiasmatic nucleus remained unchanged.
Circadian patterns of glucose and lipid metabolism-related genes were disturbed in the liver due to chronic stress.
C57BL/6 mice did not exhibit changes in serum corticosterone levels or rhythmic expressions of hepatic genes following the same stress procedure.
These findings suggest that chronic stress may disrupt liver metabolism through alterations in circadian gene expressions.

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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.

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

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