Cycles of Feeding and Fasting Drive Circadian Gene Expression in the Liver
When you eat may be just as vital to your health as what you eat, researchers at the Salk Institute have discovered. Their experiments in mice revealed that the daily waxing and waning of thousands of genes in the liver—the body's metabolic clearinghouse—is mostly controlled by food intake and not by the body's circadian clock as conventional wisdom had it.
"If feeding time determines the activity of a large number of genes completely independent of the circadian clock, when you eat and fast each day will have a huge impact on your metabolism," says the study's leader Satchidananda (Satchin) Panda, an assistant professor in the Regulatory Biology Laboratory.
To investigate how much influence rhythmic food intake exerts over the hepatic circadian oscillator, graduate student and first author Christopher Vollmers put normal and clock-deficient mice on strictly controlled feeding and fasting schedules while monitoring gene expression across the whole genome.
They found that putting mice on a strict 8-hour feeding/16-hour fasting schedule restored the circadian transcription pattern of most metabolic genes in the liver of mice without a circadian clock. Conversely, during prolonged fasting, only a small subset of genes continued to be transcribed in a circadian pattern even with a functional circadian clock present.
In mammals, the circadian timing system is composed of a central circadian clock in the brain and subsidiary oscillators in most peripheral tissues. The master clock in the brain is set by light and determines the overall diurnal or nocturnal preference of an animal, including sleep-wake cycles and feeding behavior. The clocks in peripheral organs are largely insensitive to changes in the light regime. Instead, their phase and amplitude are affected by many factors including feeding time.
"The liver oscillator in particular helps the organism to adapt to a daily pattern of food availability by temporally tuning the activity of thousands of genes regulating metabolism and physiology," says Panda. "This regulation is very important, since the absence of a robust circadian clock predisposes the organism to various metabolic dysfunctions and diseases."
"Our study represents a seminal shift in how we think about circadian cycles," he says. "The circadian clock is no longer the sole driver of rhythms in gene function, instead the phase and amplitude of rhythmic gene function in the liver is determined by feeding and fasting periods—the more defined they are, the more robust the oscillations become."