Disruptions to our circadian clocks – the internal molecular timekeepers “ticking” in nearly every cell of our body– can lead to a wide range of health problems, from sleep disturbances to diabetes and cancer. But scientists were not sure about which substances in the body can “shift” these clocks forward or backward and –when they are changed – potentially cause such disruptions.
A study from Prof. Gad Asher’s lab at the Weizmann Institute of Science in Rehovot, just published in Nature Communications under the title “Steroid hormone receptors through Cry2 are key players in the circadian clock response to serum,” discovered that sex hormones play a central role in aligning the cellular clocks with one another and with the environment.
The research team, led by Drs. Gal Manella, Saar Ezagouri, and Nityanand Bolshette, showed that female sex hormones – especially progesterone – together with the stress hormone cortisol, have a dramatic effect on the clocks.
Asher, an internal medicine physician who since 2006 has devoted all his time to research – first at the University of Geneva and since 2011 at Weizmann Institute of Science – today works as a senior researcher in the biomolecular sciences department. “I was a physician at Tel Aviv Sourasky Medical Center, but since I always worked in labs, I decided to go into full-time biomedical research at Weizmann,” he told The Jerusalem Post in an interview. “I had to compromise.” Fortunately, his lab was not destroyed last summer by the Iranian ballistic missile attack, unlike others.
“It’s been known for about 30 years that there’s a clock in every cell in the body. If there is no coordination among them and between organs, various medical conditions can arise. Comprehensive and detailed mapping of what substances in the blood can affect the clocks used to take months; now it can be much faster.”
Developing a molecular understanding of the circadian clock
Asher and his team are interested in a molecular understanding of how these clocks operate on the cellular level and in intracellular organelles, how the central clock in the brain synchronizes the clocks in other organs, and what the reciprocal relations involving circadian clocks, metabolic processes, and nutrition are. Their groundbreaking studies have important implications for the treatment of many physiological phenomena, such as sleep disorders, excessive weight gain, diabetes, and aging.
The main circadian clock, which is found in the brain, synchronizes millions of clocks that are scattered in every cell of our bodies. Recent breakthroughs have uncovered an intricate interplay between circadian rhythms and metabolism. Our internal clocks not only influence our metabolism throughout the day – they are also shaped by our metabolic state.
They took blood from rodents and worked on it in vitro [in a glass dish]. The proteins are mostly the female hormones progesterone and estrogen – so the influence is likely to be dominant in women.
They function in all mammals, including humans, on a 24-hour cycle and control a wide variety of physiological processes in our bodies, including times of wakefulness and sleep; and daily changes in heart rate, blood pressure, kidney function, body temperature, and hormonal secretions.”
The team previously reported that hypoxia – low levels of oxygen in the body tissues that occur in obstructive sleep apnea (OSA), shifts the clock in a time- and tissue-specific manner and consequently elicits inter-tissue circadian clock misalignment, which might aggravate OSA symptoms.
It’s known that circadian clocks are affected not only by external signals such as sunlight but also by signals carried through the bloodstream, but until now, these triggers have not been fully mapped, and there was no certainty about the component within the clock that serves as their “point of entry.” The reason is that researchers lacked a precise method for tracking the clock’s response to different signals over a full 24-hour cycle.
In recent years, Asher’s lab – a world leader in the study of the molecular mechanisms of circadian clocks – developed an ingenious method that uses an array of human cells, each representing a different “time of day.” Their groundbreaking studies have important implications for the treatment of many physiological phenomena, such as jet lag, sleep disorders, excessive weight gain, diabetes, and aging.
“We are interested in a molecular understanding of how these clocks operate on the cellular level and in intracellular organelles, how the central clock in the brain synchronizes the clocks in other organs, and what the reciprocal relations are involving circadian clocks, metabolic processes, and nutrition,” Asher said.
The clock network can be compared to a wall lined with clocks showing the current time in major cities around the world. The new approach made it possible for the researchers – for the first time and with unprecedented accuracy – to map how the cellular clocks are synchronized by blood-borne signals.
Unexpectedly, they discovered that the protein Cry2, rather than Per2 as previously believed, plays a central role in the response to serum [the clear, liquid part left when red cells and clotting proteins are removed] and specifically to steroid hormones, regardless of its effect on the length of the clock. “We found that Cry2 has a central role in the response to serum and specifically to steroid hormones, irrespective of its effect on the clock period length,” Asher explained.
“The levels of sex hormones change throughout life – during menstrual cycles, pregnancy, hormone therapy, contraceptive use, and various disease states. These conditions are also known to be linked to disturbances to circadian clocks,” he noted. “Our new findings suggest that these disturbances are linked to interactions between sex hormones and the mechanisms that synchronize circadian clocks.”
They identified a major role for steroid hormone receptors, including the glucocorticoid, progesterone, androgen, and estrogen receptors. Triple inhibition of glucocorticoid, progesterone, and estrogen receptors completely abolished the response to serum, suggesting that these steroid hormone receptors cover the lion’s share of the clock response to serum-induced phase resetting. Yet it does not exclude the presence of additional, less-potent blood-borne time signals.
“We shed light on the potential involvement of additional pathways that hitherto were not implicated in clock resetting. As a result, Asher concluded, “our findings merit further investigation and support the possibility that these signaling pathways are implicated in clock resetting in humans. Notably, androgens have been implicated in the control of circadian behavior, yet less is known about their resetting effect on peripheral clocks.”