Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 293

behavior, 164,186,187 which likely contributes to these pathologies. Lastly,
recent work indicates that social jetlag is associated with obesity in humans. 22

4.3.1 Environmental models
Simulated shift work in humans affects postprandial hormone levels and
metabolic state in a manner that depends on the nutritional content of
the meal. 188,189 Simulated conditions of circadian misalignment using forced
desynchrony in humans provided isocaloric meals adversely affects meta-
bolic state, with decreased leptin and increased glucose. 190 Adding sleep
deprivation to this type of forced desynchrony protocol also produces
adverse metabolic consequences in humans, with decreased resting metab-
olism and increased postprandial glucose levels. 191 Moreover, simulated
eastward or westward travel in humans caused increased insulin and glucose
levels, increased carbohydrate oxidation, and decreased protein oxida-
tion. 192 Simulated shift work in rodent models is likewise linked to meta-
bolic syndrome and obesity, 33,193,194 which may be related to food intake
at inappropriate times. 195,196 Likewise, exposure of mice to non-24 h LD
cycles results in accelerated weight gain, obesity, and higher glucose and
insulin levels. 197,198 The adverse effects of circadian disruption are also evi-
dent during development, with repeated shifts in the LD cycle predisposing
rats to sex-dependent metabolic consequences during adulthood, including
increased adiposity, hyperinsulinemia, reduced glucose tolerance, and
increased insulin secretion. 199 Moreover, rodents held under constant light
display dysfunctional changes in metabolic state, adiposity, and feeding
behaviors. 200-203 Light at night in mice also leads to a change in the time
of food intake, increased body mass, and reduced glucose tolerance, which
can be ameliorated with properly phased food intake. 54

4.3.2 Genetic models
Mice with a dominant negative mutation in the clock gene display a change in
the timing of food intake, increased body weight gain, increased adiposity,
increased cholesterol, triglycerides, and insulin levels, reduced levels of
orexin and ghrelin, and impaired pancreatic function. 204-206 A metabolic
phenotype with hypotension and renal defects is also evident in clock /
mice. 207 Moreover, bmal1 mice display a diabetic phenotype, insulin

resistance, ectopic fat formation, increased circulating fatty acids, impaired
pancreatic function, and a lowered genetic profile for adipose
function, 83,203,205,206,208-210 with impaired metabolic function evident
when bmal1

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is restricted to the pancreas, 205,211 liver, 212,213 or adipose

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