Multimodal Regulation of Circadian Glucocorticoid Rhythm by Central and Adrenal Clocks

Abstract

Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases.

Keywords: adrenal gland; circadian clock; circadian rhythm; glucocorticoid; hypothalamic-pituitary-adrenal axis.

Figure 1.

Schematic representations of the mammalian circadian timing system. (a) Circadian molecular clock in mammals. The mammalian circadian oscillator is composed of two interlocking transcription/translation feedback loops, designated as core and auxiliary loops, to produce precise rhythms of cyclic gene expression. (b) Hierarchical organization of the mammalian circadian system. The SCN functions as the master pacemaker responsible for the coordination of multiple clock networks throughout the body. Local oscillators in extra-SCN brain regions and peripheral tissues, in turn, constitute tissue-specific physiological outputs. Of particular interest, circadian rhythm in adrenal GCs contributes to coordination of central and peripheral rhythms.

Figure 2.

Genome-wide circadian rhythmicity in the adrenal gland. Circadian gene expression profiles in the adrenal gland from two independent microarray studies [37, 38] are compared. Raw data are available from the Gene Expression Omnibus database (accession nos. GSE4238 and GSE54650, respectively). (a) Venn diagram for circadian genes identified using JTK_CYCLE [43]. Rhythmic gene transcripts are defined as follows: adjusted P < 0.05 for rhythmicity and amplitude >10% of mean expression level of a given gene as calculated by the JTK_CYCLE algorithm. (b) Top 30 circadian genes according to P value and their expression profiles are expressed as a heat map. (c) Tissue enrichment analysis of 240 common circadian genes using the BioGPS database (http://biogps.org). The commonly rhythmic genes overlap with 6.12% of the adrenal-enriched genes with statistical significance (P < 0.05 for overlapping). (d) Top 10 biological functions annotated by gene set enrichment analysis using Ingenuity Pathway Analysis (https://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis/) for the commonly rhythmic genes (upper). A heat map representation for cyclic expression profiles of the genes involved in synthesis of steroid is shown (lower). Raw data from GSE54650 [38] were used to construct heat maps in (b) and (d).

Figure 3.

Cooperative actions of central and adrenal clocks underlying circadian GC rhythm. The robust daily variations in circulating GC levels are achieved by multiple regulatory mechanisms. The SCN central clock regulates the adrenal rhythm by modulating the HPA axis as well as through autonomic neural inputs [autonomic nervous system (ANS)] into the gland. In addition to the central mechanisms, adrenal-intrinsic mechanisms involving the adrenal local clock also underlie the circadian GC rhythm. The adrenal peripheral clock gates adrenal sensitivity to ACTH and controls the GC biosynthesis through coordinated transcriptional regulation of a subset of adrenal steroidogenic genes.