Strengthening Circadian Signals

There is a growing body of evidence from both laboratory and field studies that disrupted
circadian function, particularly decreased amplitude and stability of rhythmic behaviors
represent significant risk factors for cardiometabolic disease (CMD) in humans. The exciting
evidence of the ubiquity of circadian clocks in all tissues and their critical role in
metabolism, not only opens up new avenues for understanding the mechanistic interactions
between central and peripheral clocks in cardiometabolic disease pathogenesis, but also to
develop therapeutic interventions to re-establish synchrony between central and peripheral
clocks with each other and with the external physical and social environments. Feeding has
been shown to synchronize clocks in peripheral tissues. Animal studies have demonstrated that
restricting feeding to the active period decreases CMD risk, while in humans decreased
caloric intake in the evening is associated with a lower body mass index (BMI). The amplitude
of melatonin can be considered a marker of robustness of central circadian function, but
melatonin also has physiological effects beyond circadian regulation throughout the body.
Recent observations have demonstrated that having a low melatonin level is a risk factor for
incident diabetes and hypertension independent of sleep duration. Together, the evidence
suggests that strategies aimed at synchronizing feeding behavior and enhancing the nocturnal
melatonin signal can positively impact cardiometabolic function.

We propose to take an innovative approach that combines the recent data on the role of
feed/fast patterns on clock regulated metabolic activity and the reemergence of scientific
interest of the central and peripheral effects of melatonin on cardiometabolic function to
elucidate the physiological and molecular mechanisms that underlie the relationship between
circadian dysregulation and obesity associated CMD risk. This will be accomplished by
strengthening the amplitude of circadian metabolic signals via meal timing and enhancement of
nocturnal circadian signaling with exogenous melatonin in overweight and obese middle aged
and older adults. In addition, this study will provide crucial information regarding the
importance of circadian timing for the design of future clinical trials on CMD in overweight
and obese adults. This is a critical time in the lifespan when circadian based strategies for
prevention and treatment are most likely to have the greatest impact on CMD risk. This
project will enroll 100 adults (40-54 years) to participate in a parallel (4 arm
intervention) placebo controlled study to determine whether a six- week program of meal
timing and/or low dose (3 mg) melatonin administration will enhance circadian amplitude and
enhance cardiometabolic function, as well as to evaluate the potential beneficial effects of
a regimen that combines both approaches. The results from this study will demonstrate novel
mechanistically based approaches for maintaining and improving circadian-metabolic health
during a critical time in the lifespan when there is a rapid increase in the prevalence of
CMD.