title: Circadian rhythms of glucocorticoid hormone actions in target tissues: potential clinical implications.
abstract: Organisms face unforeseen short- and long-term changes in the environment (stressors). To defend against these changes, organisms have developed a stress system that includes the hypothalamic-pituitary-adrenal (HPA) axis, which employs glucocorticoids and the glucocorticoid receptor (GR) for signal transduction. In addition, organisms live under the strong influence of day-night cycles and, hence, have also developed a highly conserved circadian clock system for adjusting their activities to recurring environmental changes. This regulatory system creates and maintains internal circadian rhythmicity by employing a self-oscillating molecular pacemaker composed of the Clock-Bmal1 heterodimer and other transcription factors. The circadian clock consists of a central master clock in the suprachiasmatic nucleus of the brain hypothalamus and peripheral slave clocks in virtually all organs and tissues. The HPA axis and the circadian clock system communicate with each other at multiple levels. The central clock controls the HPA axis, creating the diurnal oscillation of circulating adrenocorticotropic hormone and cortisol, and the HPA axis adjusts the circadian rhythmicity of the peripheral clocks in response to various stressors through the GR. Further, Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the GR, possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. Importantly, dysregulation in the clock system and the HPA axis may cause similar pathologic manifestations--including obesity, metabolic syndrome, and cardiovascular disease--by uncoupling circulating cortisol concentrations from tissue sensitivity to glucocorticoids.
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development-NICHD, NIH, Bethesda, MD 20892, USA. kinot@mail.nih.gov
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation / Q000187:drug effects; D001296:Audiovisual Aids; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002940:Circadian Rhythm; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D006854:Hydrocortisone