Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 93

Figure 4.1 The relationship between clock genes and the metabolism/energy require-

ments of the cell. Many energy- or metabolism-associated molecules have the capacity
to influence the clock gene cycle; on the other hand, also the output is associated with
the energy cycle of the cell (see text and [ 26 ] for details). Figure from [ 26 ] with
permission.

energetic AMP/ATP status of the cell is under circadian control. The cat-
alytic subunit alpha1 of the AMP/ATP sensor enzyme AMPK exhibits a
robust circadian rhythm of nuclear localization in mouse liver, peaking syn-
chronously with the beta2 subunit expression. The phosphorylation of
AMPK substrates Raptor-Ser792 and ACC1-Ser79 also has a diurnal
rhythm. 25 One of the first studies that showed the reciprocal connection
of AMPK with the clock system demonstrated in vitro that AMPK phosphor-
ylates Casein kinase I epsilon (an important regulator of the period length),
resulting in increased activity of this enzyme which, in turn, phosphorylates
and induces the degradation of Per2. In vivo , injection of the AMPK-activating
drug metformin leads to mPer2 degradation in peripheral tissues and a phase
advance in the circadian expression pattern of clock genes in wild-type mice