AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation

Abstract

Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.The mammalian hypothalamic suprachiasmatic nucleus (SCN) acts as a master pacemaker, aligning behavioral and physiological rhythms to light-dark cycles (1). Initially, the SCN was thought to be the only site of self-sustaining molecular pacemakers in mammals, but subsequent reports have shown such clocks to be ubiquitous (2,3). Unlike those in the SCN, clocks in non-light-sensitive organs are entrained by daily feeding (2,4,5), which

The role of clock genes and rhythmicity in the liver

“…Interestingly, Parp-1 knockout mice exhibit impaired food entrainment of peripheral clocks, suggesting PARP-1 as a mediator of food entrainment. Moreover, the adenosine monophosphate (AMP)-activated protein kinase (AMPK) that is a central mediator of metabolic signals was shown to be involved in the clock mechanism (Lamia et al, 2009). AMPK phosphorylates and destabilizes the core clock component CRY1 and may hence act on the oscillator mechanism (Fig.…”

Reciprocal regulation of carbon monoxide metabolism and the circadian clock

“…Such a mechanism has been proposed to play a role in resetting the cholinergic clock in the suprachiasmatic nucleus 36 , where heme oxygenase activity is circadian 37 . Moreover, increased cGMP levels can enhance AMP kinase (AMPK) activity 38 , which in turn may act on the clock by promoting CRY-protein degradation 39 . Activation of AMPK in the liver also represses expression of gluconeogenesis enzymes such as Pck1 and G6pc 40 , results opposite from those observed in heme oxygenase-depleted hepatocytes.…”

Horloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux

“…Le NAD + est également le cofacteur de la polyADP-ribose polymérase-1 (PARP-1), dont l'expression oscille de façon circadienne et varie en fonction de la prise de nourriture (qui module quant à elle l'activité de CLOCK) [27]. Par ailleurs, une augmentation du rapport AMP/ATP, témoin d'un ralentissement du métabolisme se produisant en situation de jeûne et au cours de l'exercice, active l'AMP activated protein kinase (AMPK) qui, en retour, phosphoryle Cry [28], favorisant ainsi sa dégradation par la protéine FBXL3 (F-box and leucine-rich repeat protein 3) et le protéasome. Ces données identifient le rapport AMP/ATP comme un acteur potentiel du contrôle circadien du métabolisme.…”