bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2019‒08‒11
three papers selected by
Gabriela Da Silva Xavier
University of Birmingham

  1. Cell Metab. 2019 Aug 06. pii: S1550-4131(19)30373-0. [Epub ahead of print]30(2): 238-250
      The importance of circadian biology has rarely been considered in pre-clinical studies, and even more when translating to the bedside. Circadian biology is becoming a critical factor for improving drug efficacy and diminishing drug toxicity. Indeed, there is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite. This suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics. Thus, it is now time that circadian factors become an integral part of translational research.
    Keywords:  ADME; chronotherapy; circadian biology; clock genes; drug metabolism; translation
  2. Endocrinology. 2019 Jul 29. pii: en.2019-00357. [Epub ahead of print]
      The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+:: Bmal1Fl/Fl KO (SCC-KO) mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone, but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO show a stronger adrenal phenotype. Parallel experiments were done using female Cyp11B2 (Aldosterone Synthase)Cre/+:: Bmal1Fl/Fl mice, adrenal cortex-specific Bmal1 null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.