If the biological “clocks” – the genetic networks controlling circadian rhythms – present in virtually every cell of our body ticked out loud, would their sound amount to a chaotic cacophony or a harmonious hum?
Until several years ago, scientists thought that the master clock in the brain brought into line all the sections of the orchestra, from the head on down. In the past few years, however, studies have shown that clocks in other organs are sometimes out of step with the one in the brain, but these clocks were collectively viewed as a uniform group. A new Weizmann Institute of Science study reveals that there are “cross-rhythms” even within that group.
A research team headed by Prof. Gad Asher of the Biomolecular Sciences Department has shown that these clocks can, under certain conditions, behave more like a jazz band, in which different instruments break into their own rhythms.
Circadian clocks in the body respond to different cues – light, food, oxygen levels, stress – but they all rely on similar molecular machinery: a self-regulating network of several genes that shuts itself off when its gene expression exceeds a certain level. In the new study, doctoral student Gal Manella led experiments to test how clocks in different peripheral tissues and organs respond to the same circadian cue: food.
The researchers fed mice at unusual times and monitored the expression of all their genes to see how their peripheral clocks and rhythms responded to the different feeding schedules. In particular they wanted to check whether the clock in the liver, an organ that plays a central role in processing nutrients, regulated the clocks and rhythms in other peripheral tissues. To this end, they used transgenic mice that lacked the liver clock and compared the findings related to these mice with those from unmodified ones.
The study revealed that the daytime feeding triggered a jam session of out-of-step rhythms in the peripheral clocks of the unmodified mice. The liver clock shifted its ticking by exactly twelve hours, in step with the shift in the feeding schedule, as did the clock in fat tissue. But overall, the clock in the liver didn’t set the pace for those of other organs.
Surprisingly, however, the scientists found that the liver clock did affect the rhythms of gene expression in other tissues, even without controlling their peripheral clocks. They thus concluded that the liver clock served as a buffering mechanism that protected various organs from nutritional disruptions, without connection to their clocks.
The study’s findings may be relevant to a variety of situations in which the interaction between peripheral clocks and other rhythms in the body is disturbed. For example, understanding these interactions may help clarify the causes of an increased incidence of disease in shift workers, whose work patterns upset their circadian clocks. It might also help us understand the effects of diets that alter the timing of meals, such as intermittent fasting. And it might provide insights into metabolic diseases characterized by disrupted communication between body organs: high blood glucose, obesity, and other disorders collectively known as the “metabolic syndrome.”
The research team included Dr. Elizabeth Sabath, Dr. Rona Aviram, Vaishnavi Dandavate, Saar Ezagouri, Dr. Marina Golik, and Dr. Yaarit Adamovich, all of Weizmann’s Biomolecular Sciences Department.
