Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 115

arcuate and dorsomedial hypothalamic nuclei, 15,78 central amygdala, 25,79
and cerebellum. 80,81 By contrast, circadian oscillations in few brain struc-
tures, such as the SCN and the hippocampus, are less sensitive to timed
mealtime. 14 The cerebral oscillators or clocks that are sensitive to mealtime
define a feeding-entrainable network, some of them being likely involved in
the mechanisms of behavioral meal anticipation, as evoked above.
2.5. SCN: The master light-entrainable clock is sensitive to
metabolic and reward cues
The mammalian clock machinery described in Section 1 is present in cells of
the master suprachiasmatic clock. Compared to the rapid dampening of cir-
cadian oscillations in peripheral organs, the very robust self-sustained rhyth-
micity of suprachiasmatic cells, even when isolated in vitro , involves likely a
strong intercellular coupling. 82
Activity of mitochondrial cytochrome oxidase in suprachiasmatic cells is
higher during daytime, while lactate dehydrogenase activity increases at
night. 83,84 Because the daily variations of cytochrome oxidase activity are
no longer detectable in constant darkness, this suggest that the photic inputs
play a regulatory role in the rhythmicity of this metabolic process. 83
The capacityof the suprachiasmatic cells togenerate endogenous rhythmic-
ity was initially demonstrated ex vivo and in vitro with a metabolic readout,
namely, the circadian rhythm of 2-deoxyglucose uptake. 85 Of interest, cul-
tured fibroblasts cannot generate such metabolic rhythmicity, despite syn-
chronized clock gene oscillations. However, sustained oscillations of
2-deoxyglucose uptake can be triggered in fibroblastswhen they are cocultured
without physical contact with immortalized suprachiasmatic cells. 86
Another powerful demonstration of self-sustained rhythmicity generated
by the SCN came from the circadian rhythm of neuronal firing rate in
suprachiasmatic slices kept in vitro . 87 Electrical properties of neurons are con-
trolled by various regulatory mechanisms, such as conductances of voltage-
gated ion channels. Inhibition of oxidative phosphorylation or glycolysis
blocks the Na/K pump to depolarize resting potential and increase spontane-
ous firing in suprachiasmatic cells, thus indicating a metabolic modulation of
the Na/K pump. 88 However, the connection between the molecular clock
and the rhythmic electrical activity within the master clock remained elusive.
It turns out that redox rhythmicity, by itself driven by the molecular clock-
work as aforementioned, has a direct influence on the excitability of sup-
rachiasmatic neurons via a modulation of K þ conductance. 89