Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 292

oxidative stress levels. 120,121 Light at night in rodent models is also associated
with increased tumorigenesis 117,118 and changes in oxidative stress. 122 Given
the role of melatonin suppression in mediating these effects, it is perhaps
not surprising that manipulations of day length, which affect the duration
of melatonin secretion, can influence tumor growth in rodent

models. 119,123,124

4.2.2 Genetic models
The circadian clock regulates myriad components of cell cycle and meta-
bolic pathways and altered circadian gene expression has been detected in
a variety of cancers (reviewed in Ref. 125 ) . Of the circadian clock mutant
models, per mutant and knockout mice display a pronounced phenotype,
with molecular deregulation of cell cycle and metabolic pathways, increased
risk for spontaneous tumor growth, and accelerated growth in induced
tumor models. 110,126-129 Furthermore, per overexpression in tumor cell cul-
tures retards growth while downregulation increases growth. 126,129-132
Knockout mouse models for bmal1 and cry also display increased risk for
spontaneous and induced tumor growth, 110 highlighting the overall impor-
tance of the circadian clock in the proper regulation of the cell cycle and
tumor growth (but see Ref. 133 ) . Furthermore, both bmal1 and cry play a
role in regulating oxidative stress, with bmal1 deficiency increasing sensitiv-
ity and ROS levels 83,134,135 and cry deficiency reducing sensitivity in p53
knockout mice. 136 Associations between clock gene polymorphisms in
humans and risk or severity of cancer have also been reported

( clock , 137-139 npas2 , 140,141 per3 , 142,143 cry1 , 139 cry2 , 144,145 and timeless

146

).

4.3. Metabolic syndrome, obesity, and gastrointestinal
problems
Metabolic function and feeding processes are regulated by the circadian
clock. 147 Across a variety of cultures and occupations, shift workers display
a higher incidence of a variety of risk factors for metabolic syndrome, 148-151
including increased weight gain and obesity, 152-162 altered free fatty acid,
cholesterol, and triglyceride levels, 155,156,158,163-167 altered lipid and carbo-
hydrate metabolism, 155,166,168-171 insulin resistance, glucose tolerance, and
diabetes, 155,169,172-175 with changes in appetite-regulating hormones,
growth hormones, and cortisol level. 152,176-179 In addition, shift workers
display increased rates of several gastrointestinal disorders, including
increased incidence of gastrointestinal discomfort, ulcers, and irritable
bowel syndrome. 180-185

Shift workers also display altered feeding