Manipulating the metabolic clock
22 May, 2012
Two research groups in the United States have published research into modifying our so-called ‘clock’ genes to adjust circadian rhythms – the 24-hour cycle of biological processes that govern day and night activity.
It seems a little adjusting of our internal clocks may hold the key to conquering a myriad of disorders such as jet lag, sleep disorders, cardiovascular disorders and even metabolic diseases like obesity.
Molecular regulation of internal clocks
In mammals, including humans, most if not all tissues display a self-sustaining circadian molecular 24-hour-period pacemaker that is responsible for aligning rhythms in various physiological functions. The suprachiasmatic nucleus (SCN) of the hypothalamus (part of the brain) functions as the master regulator of circadian rhythms, synchronising behavioural and physiological responses with whether it is light or dark.
Two nuclear receptors also influence internal clocks
Just over 10 years ago, scientists discovered that, as well as the time of day, two receptors, REV-ERB-α and REV-ERB-β, also influence our internal clocks. These receptors are able to suppress the expression of certain genes to send the body into a dormant state.
Now, the two research groups have both studied how our internal clocks are regulated at the molecular level and how the two nuclear receptors REV-ERB-α and REV-ERB-β are controlled in regulating clock genes, affecting our activity levels and metabolism.
Lack of receptors in mice disrupted circadian behaviours
The first study group led by Ronald Evans from the Gene Expression Laboratory at the Salk Institute for Biological Studies in California shows that mice that lacked these receptors showed disrupted circadian behaviours, such as wheel-running at odd times and deregulated fat metabolism. In their research, the team writes: “Disruption of rhythm spawns a range of problems from jet lag, to more profound sleep disorders, obesity, metabolic disease, immune function and cancer.”
Two synthetic agents that alter circadian rhythms in mice
The second study group led by Thomas Burris from the Department of Molecular Therapeutics at the Scripps Research Institute in Florida has identified two synthetic agents that can alter circadian rhythms in mice. This may eventually be useful for the treatment of sleep disorders and metabolic diseases, such as obesity or diabetes in humans.
Potential treatments for metabolic diseases and jet lag
The synthetic agents bind to the REV-ERB-α and REV-ERB-β receptors and modify the circadian expression of core clock genes. In turn, related metabolic processes are changed, resulting in increased energy expenditure by the study mice. Obese mice treated with the compounds show reduced fat mass and improved symptoms associated with obesity. As well as offering potential treatment options for metabolic diseases, Burris and colleagues suggest that these compounds could be used to improve jet lag by aligning body clocks to a new time zone.
- 22 May 2012