Choice of feeding time may influence liver’s biological clock, study says

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The timing of food intake is a major factor driving the rhythmic expression of most genes in the mouse liver, Texas A&M University researchers report April 16 in the journal Cell Reports.

The findings demonstrate that body-wide signals driven by rhythmic food intake significantly contribute to driving rhythms in liver metabolic functions and gene expression independently of the liver and clock.

“In contrast to the prevailing model in the field currently, our findings indicate that feeding times do more than just synchronize the molecular clock in different organs — they actually can regulate rhythmic gene expression in parallel of the clock,” says senior study author and Texas A&M biologist Jerome Menet, whose lab within the Center for Biological Clocks Research studies the mammalian circadian clock. “This raises the interesting hypothesis that eating at the wrong time of the day, which is prevalent in shift-workers for example, can desynchronize rhythmic gene expression and lead to pathologies.”

Nearly every mammalian cell harbors a molecular circadian clock that drives rhythmic gene expression to coordinate daily cycles in metabolism, physiology and behavior. These clocks are synchronized by the master circadian pacemaker located in a brain structure called the suprachiasmatic nucleus (SCN). The SCN uses multiple cues, such as rhythms in neuronal signaling, hormone secretion, body temperature and food intake, to synchronize outlying clocks located in various organs throughout the body, ensuring that they are all properly entrained to the environment. 

Entrained peripheral clocks are thought to then regulate rhythmic gene expression in a cell-autonomous manner — that is, independently within each cell — to start tissue-specific circadian transcriptional programs that control the rhythmicity of biological processes. In contrast to current models, the new findings show that rhythmic food intake largely drives rhythmic gene expression independently of the cell-autonomous molecular clock in the liver. 

To examine the role of rhythmic food intake in circadian biology and rhythmic gene expression, Menet and his team fed mice arrhythmically — at night only or in an unrestricted manner for five weeks, then collected the livers of the mice at different times of day and examined the expression of liver genes.

Compared to unrestricted feeding, arrhythmic feeding disrupted oscillations in the expression of 70 percent of cycling liver genes without affecting the core molecular clock in the liver. Moreover, the timing of food intake regulated many metabolic pathways in the liver, including those involved in cholesterol and glycogen synthesis. Taken together, the findings suggest that the master circadian clock in the SCN does not act solely to synchronize peripheral circadian clocks but instead contributes more generally to circadian transcriptional programs throughout the body.

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