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clock and its synchronization to light canbemodifiedby both thenegativemet-
abolic drive associatedwith hypocaloric feeding and the positive hedonic drive
associated with palatable pellets. However, the direction of the modulation of
light resetting is opposite: the amplitudeof the circadian responses to light of the
master clock are increased and reduced by hypocaloric and food-related reward
cues, respectively. As discussed elsewhere, the orexinergicneurons in the lateral
hypothalamus can integrate bothkinds of feeding-related cues andmay provide
a main modulatory afferent pathway to the SCN.
26
Together, these findings highlight the fact that the multi-oscillatory cir-
cadian network is involved in the daily variation of metabolism at all levels of
the circadian system. Moreover, mealtime and other nutritional cues can act
in circadian timing have deleterious consequences on metabolic health, as
detailed in the next part.
3. PATHOLOGY
3.1. Circadian disturbances are associated with metabolic
dysfunctions
In most instances, circadian disturbances result from an altered endogenous
clockwork or from altered exogenous timing cues. Mutations or KO of
clock genes have been frequently linked with disturbances of metabolism.
For instance,
Clock
mutant mice show increased adiposity, possibly due to
synthesizing nocturnal melatonin and having disrupted expression of
Clock
in the liver and skeletal muscles show lower glucose tolerance and signs of
impaired glycolysis and gluconeogenesis.
114
Cry1
/
;
Cry2
/
mice suf-
fer from hypertension.
115
Per2
(
Brdm1
) mutant mice have impaired glucose
homeostasis, characterized with hypoglycemia and hyperinsulinemia rela-
mice have reduced lipid stores.
35
Knockout of
Rev
-
erba
leads to increased adiposity and chronic hyperglyce-
mia, despite the same daily energy intake of chow diet and daily level of
Clock
mutation in mice leads to increased fatty acid oxidation and decreased
mild hypoglycemia in the afternoon and increased glucose tolerance.
118
Mice with pancreas-specific deletion of
Bmal1
mutant mice are intolerant
/
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