Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 118

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
on the timing of various clocks ( Fig. 5.1 ). This may explain why alterations
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
the hypoactivity and hyperphagia reported above. 27 These mutant mice also
display reduced gluconeogenesis, but enhanced insulin sensitivity. 113 Mice
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-
tive to wild-type mice, 116 while Per2 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
motor activity as those in wild-type littermates. 29 A cardiomyocyte-specific
Clock mutation in mice leads to increased fatty acid oxidation and decreased
cardiac efficiency. 117 Mice bearing a liver-specific deletion of Bmal1 show a
mild hypoglycemia in the afternoon and increased glucose tolerance. 118
Mice with pancreas-specific deletion of Bmal1 mutant mice are intolerant
to glucose and have diminished insulin secretion 119 ( Fig. 5.3 ) .

/