Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: Implications for cardiometabolic diseases

Tomoshige Kino, George P. Chrousos

Research output: Chapter in Book/Report/Conference proceedingChapter

39 Citations (Scopus)


Glucocorticoids, the end-products of the hypothalamic-pituitary-adrenal (HPA) axis, influence the functions of virtually all organs and tissues through the nuclear glucocorticoid receptor (GR). Circulating levels of glucocorticoids fluctuate naturally in a circadian fashion under the strong influence of the hypothalamic suprachiasmatic nucleus (SCN) circadian CLOCK system, and regulate the transcriptional activity of the GR in the brain and peripheral target tissues. We recently reported that the basic helix-loop-helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids. Interestingly, mild evening elevations of corti-sol, as occurs in chronic stress situations, and frequent uncoupling of the SCN CLOCK-directed HPA axis from the daily oscillation of target tissue sensitivity to glucocorticoids, as happens in trans-time zone travel and night shift work, produce functional hypercortisolism and, hence, multiple components of the metabolic syndrome with resultant cardiovascular complications.

Original languageEnglish
Title of host publicationPediatric Adrenal Diseases
EditorsLucia Ghizzoni, George Chrousos, Mohamad Maghnie, Marco Cappa, Sandro Loche
Number of pages11
Publication statusPublished - 1 Dec 2010

Publication series

NameEndocrine Development
ISSN (Print)1421-7082
ISSN (Electronic)1662-2979


ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Endocrine and Autonomic Systems

Cite this

Kino, T., & Chrousos, G. P. (2010). Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: Implications for cardiometabolic diseases. In L. Ghizzoni, G. Chrousos, M. Maghnie, M. Cappa, & S. Loche (Eds.), Pediatric Adrenal Diseases (pp. 116-126). (Endocrine Development; Vol. 20).