How the body clock affects metabolism

For many, the clocks going back this weekend means a welcome extra hour in bed. But, the changing of time zones affects more than just how rested you feel on the 2 days of the year we change between Greenwich Mean Time and “Summer” or “Winter” time. In fact, when the clocks spring forward in March, there is a significant uptick in the number of serious cardiovascular incidents - like heart attacks - and as the clocks fall back in the autumn, rates of mental illnesses like depression and seasonal affective disorder surge. This is all to do with the change having a knock on effect on our internal body clock: the inbuilt timing mechanism which many living organisms use to trigger biological processes to keep them alive. This is also known as our circadian rhythm. James Tytko spoke with Joe Bass at Northwestern University, who has been studying how circadian rhythms not only impact on the ability of animals to know when to fall asleep and when to wake up, but also on their relationship with food…

Joe - Circa comes from the Latin, which is diem, which is about a day. So Circa diem is about a day. And that 24 hour period of our waking up and feeling tired each day corresponds with the rotation of the planet. It turns out that all forms of what we call photosensitive life, which means all life that have the ability to detect light, have evolved a mechanism internally to anticipate the 24 hour rotation of the Earth. This was discovered hundreds of years ago by a biologist in France who took a plant called the Mimosa Plant, which exhibits leaf opening and closing. Every 24 hours, he placed that plant in a dark box and was able to prove that the leaves continued to open and close in the same pattern. In a 24 hour period that matches the rotation of the earth.

James - It's so interesting, and I suppose the question then becomes, how do we utilize this knowledge to our benefit?

Joe - Right. Between the early 1970s and the late 1990s, the entire repertoire of genes that regulate timing became known to us and and were available in hand. And once those genes had been identified in the animal kingdom in mice, it became possible for us to begin to ask questions about how this system is intertwined with systems that govern processes such as not only sleeping, but why is it that we get hungry at certain times of day? How does our heart rate change across the day? Now, one of the key moments occurred when such mice were available at Northwestern. These animals had abnormalities in their body weight, and so we began to systematically test whether defects in the molecules that control the sleep system and sleep wake cycles might also control metabolism. And in doing so, we observe that animals that have disturbance in their mechanism for timing have reproducible defects in the control of energy balance, which results in obesity if they're provided high fat diet and in the control of blood sugar, which results in diabetes. We use a variety of different approaches. We can manipulate genes that are in the place in the brain that responds to the sunrise each day, which is called the central clock or the master clock. Or we can get more sophisticated and manipulate that same alarm clock, so to speak in the body, in the cells that regulate energy balance. There may be an alarm clock, so to speak, within our cells that can metabolize nutrition, either store it or burn it.

James - So could you contextualize it, just what sort of impact time restricted feeding has on weight?

Joe - So we had special chambers built, which dispense food by computer systems very precisely corresponding with when the lights go on and off in the environment in which the animal is housed. So here we can control both the light cycle and the dispensing of food that is either normal food or high fat food, and we can compare what are the effects of the change in eating time with regard to the magnitude of obesity that the animal experiences and do the genes that control timing influence the magnitude of weight gain. So using that approach, we were able to definitively show that if an animal eats when it should be asleep, they have a tendency, even if they've eaten the exact same amount that they could eat when they were awake, they gain more weight.

James - Fascinating. And how transferrable are the results you found in mice, in people?

Joe - Well, that's really a million dollar question. Our genomes are 98% conserved across rodents and humans. That doesn't mean that the exact information that we have in hand will in its entirety transfer. It simply means that we've gained inroad into recognition that there's something about the intrinsic timing system and our response to nutrition that needs to be taken into consideration for questions such as, in the situation in which somebody has diabetes for instance, how do we align the delivery of insulin with food? Or what is the effect of eating at different times or shift work on metabolism? And we know that in individuals in which the system's already stressed or pushed by virtue of the development of metabolic disease, these questions become more apparent and immediate from a clinical standpoint. We know, for instance, in the hospital that individuals who cannot eat any longer and are delivered nutrient through a tube, the the tube feedings are often delivered when the individuals are asleep or at night. And almost universally, these individuals develop very severe metabolic complications. They have fat in their liver, they have a requirement for a great deal of insulin. So my hypothesis would be that the reason that misalignment of feeding and light cycles may lead to adverse metabolism, not only weight gain but also the ability to handle nutrients at different times of day, has something to do with the clock system that we have begun to dissect.