a, Glucose homeostasis is regulated by the interplay between
non-autonomous circadian control — which affects glucocorticoid hormone
levels through the brain and the hypothalamic–pituitary–adrenal
(HPA) axis — and autonomous oscillatory regulation of these
hormones’ signalling in peripheral tissues such as the liver. Lamia
et al.4
report that the clock-repressor protein Cry plays a central part at both of
these levels. b, In the liver, the clock-activator proteins Clock
and Bmal1 increase Cry transcription, which downregulates gluconeogenesis both
by interacting with — and so inhibiting — glucocorticoid
receptors (GRs), and by reducing the expression of the Pck1 enzyme. As is
typical of the clock machinery, high levels of Cry also downregulate Clock and
Bmal1 transcription in a negative feedback loop, thus reducing its own levels
and so promoting gluconeogenesis during the dark phase of the light–dark
cycle.