Circadian Clocks, Food Intake, and Metabolism - Progress in Molecular Biology and Translational Science - page 123

of metabolic hormones in mice fed with high fat are attenuated, with higher
and lower plasma levels of leptin and corticosterone, respectively. 137,154 The
daily or day-night variations in clock gene expression of peripheral tissues in
high-fat fed mice have been found to show either major 154,155 or minor
changes. 29,156
The mouse line carrying the mutation db , which invalidates the leptin
receptor, is a classical model of obesity associated with severe diabetes
mellitus and hypertension. The amplitude of activity-rest rhythm and blood
pressure is dampened in db / db mice. 157,158 The characteristics of the clock
gene oscillations in the liver are significantly altered compared to those
observed in db /

control mice. 157 Experimental type 1 diabetes induced
by streptozotocin, which destroys pancreatic b cells, is associated with sev-
eral circadian disorders. In particular, the amplitude of oscillations of clock
genes is reduced in the liver of diabetic mice. 159 Moreover, the phase-
delaying effects of light are increased in streptozotocin-treated mice. 160 In
both cases, acute treatment with insulin normalizes circadian alterations.
Obesity in humans is associated with a more flattened and fragmented
rhythm of wrist temperature. 161 Moreover, the daily variations in glucose
tolerance, which usually decrease throughout daytime in lean subjects, are
reversed in obese subjects with or without type 2 diabetes. 162 At a molecular
level, clock gene mRNAs in visceral adipose tissue have been correlated
with adiposity, at least in women. 163,164 Using serial biopsies of white adi-
pose tissue in the same individuals, no significant change is detected in the
characteristics of clock gene oscillations in overweight/obese patients with
or without type 2 diabetes, as compared to lean subjects. 165 This study thus
contrasts with the majority of findings in animal studies reported above.
Whether the differences are due to the type of white adipose tissue (e.g.,
subcutaneous vs. retroperitoneal), the severity of the metabolic diseases,
or interspecific differences clearly warrants further investigations.

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4. CHRONOTHERAPEUTICS
4.1. Pharmacology
Besides taking into account the pharmacokinetics of drugs according to the
time of the day to improve their efficiency and reduce their side effects
(chronopharmacology), targeting drugs that affect the circadian system
(so-called chronobiotic drugs) is an emerging and active field of pharmacol-
ogy. Below are mentioned a few examples of recent advances in that
domain, reviewed elsewhere in detail. 166