Two groups of scientists have identified a gene that they are describing as 'the missing link' between the body's biological clock and metabolism. The studies, published in the journal Cell, found that a gene called SIRT1, whose activity is modified by the body's metabolic state and was previously known to help control the process of ageing, also plays a key role in regulating the internal clock. This important discovery helps to explain how the body regulates essential functions such as hormone production, body temperature and blood pressure, and may eventually lead to drugs to combat metabolic disorders, obesity or diabetes.
The body's internal timing system is known as the circadian clock - after the Latin term for 'around a day'. It controls important fluctuations in bodily processes over a roughly 24-hour period, synchronising them with sleeping and feeding cycles. For example, hormones to make you feel drowsy are produced after dark and many essential processes such as cell regeneration are regulated by genes that are turned on and off in rhythm with the body's circadian cycle. In mammals, the master clock is a pair of tiny structures in the brain called the suprachiasmatic nucleus or SCN. The SCN responds to cycles of light and dark, and sets the circadian cycle accordingly. In addition, many cells throughout the body act as peripheral clocks, with their circadian cycle kept under the control of a complex network of genes that are turned on and off rhythmically. A key component of this network is a gene called CLOCK, which turns genes on by modifying their physical structure.
The peripheral cellular clocks are particularly sensitive to feeding patterns, and it is the mechanisms behind this that the two research groups sought to understand. Professor Paolo Sassone-Corse, who led one of the teams, explained: 'we have all noticed in an intuitive manner that the body requires more energy at certain times of the day. That is why we have lunch or dinner - there is cyclicity in feeding behaviour and energy requirement. That suggests there must be a link between the clock and metabolism. Now, in SIRT1 we have found a molecular connection between the circadian machinery and metabolism'. SIRT1 is only active when a molecule called NAD+ is present. NAD+ production is controlled by the levels of nutrients in a cell. Therefore, SIRT1 is turned on and off by feeding patterns. When it is active, SIRT1 acts in opposition to CLOCK, turning off the genes that CLOCK turns on.
Defects in the circadian cycle are linked to a variety of health problems including insomnia, depression, coronary heart disease, metabolic disorders, obesity and diabetes. Professor Sassone-Corsi hopes that 'SIRT1 or CLOCK might make useful drug targets. Not today or tomorrow, but in the future'.