Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 124

Agomelatine is an antidepressant drug with melatonergic (MT1/MT2)
agonist and 5-HT(2C) receptor antagonist properties. Because both mela-
tonin and serotonin are known regulators of the master clock and possibly
secondary clocks, part of the antidepressant properties of agomelatine can be
mediated by its resynchronizing effects on circadian rhythms. Furthermore,
physiological doses of melatonin stimulate the activity of several antioxidant
enzymes. 167 In the case of the metabolic syndrome, such melatonergic com-
pounds may help to correct the altered sleep-wake cycle. 168
With respect to the clock gene machinery, REV-ERB ab are among
the rare circadian factors with a known endogenous ligand (i.e., heme). Syn-
thetic REV-ERBs ligands recently developed have significant effects on
clock gene expression and less clear resetting effects, as they decrease noc-
turnal activity in mice, rather than shifting the sleep-wake cycle. Neverthe-
less, some of these promising compounds have been shown to improve the
metabolic profile of obese mice. 169,170 Other hopeful targets to cure meta-
bolic disorders are the closely related members of the ROR family. 171

4.2. Food composition and feeding time
Even if most animal studies reported above concerned either chow or high-
fat diet, the nature of diet-derived nutrients can play a role in the control of
peripheral circadian timing. For instance, the daily rhythm of sterol regula-
tory element-binding protein-1 expression in the liver, where it regulates
lipid metabolism, shows differential phase shifts according to various

macronutriment regimens (i.e., standard vs. high-carbohydrate, -fat,

or -protein). 172
Several works highlight the fact that excessive food intake during the
resting period is deleterious for metabolic health and, conversely, that
avoiding it leads to beneficial effects in case of metabolic diseases. Zucker
rats display a phase-advanced rhythm of food intake, which begins in the
afternoon and not the evening (lights off ), as in control rats. It is interesting
to note that if food intake is limited exclusively to night (normal feeding
period in rats), the overweight of Zucker rats is reduced by 23% compared
to those that have a free access to food, despite similar energy intake for the
two groups of rats. 149 In the case of db / db mice that are obese and severely
diabetic, restricting food access to the dark period not only restores a robust
rhythm of rest-activity but also ameliorates plasma glucose, insulin, and
triacylglycerols. 157