Christos Mantzoros, MD, is Clinical Research Overseer of the Department of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center (BIDMC). Over the past 14 years, Mantzoros has studied the leptin hormone, which controls appetite and satiety, publishing more than 110 original papers and several book chapters on the subject.
In an article in the March 2 Advance On-line issue of the Proceedings of the National Academy of Sciences (PNAS), Mantzoros, together with colleagues from the Sleep Disorders Research Program at Brigham and Women's Hospital, describe new findings that help explain why night-shift workers are at increased risk of metabolic and cardiac disease, including obesity, diabetes and hypertension. And, among their key discoveries, is the important role that leptin plays.
What led you and your coauthors to pursue this study?
It's been widely observed that individuals whose sleep-wake cycles are chronically disrupted - people who work the night shift or individuals who frequently travel abroad and are therefore constantly adjusting to changing time zones - are at higher risk for obesity as well as for diabetes and cardiovascular disease. Knowing that leptin rises and falls based on circadian rhythms, we wanted to find out if leptin levels were low in people who had shifted their behavioral rhythms, such as being awake at night.
How did you actually conduct the study?
We recruited 10 healthy volunteers to spend 10 days in a sleep laboratory under carefully controlled conditions. Day by day, we adjusted their sleep-wake routines and their eating routines until they reached the point where their bodies' circadian rhythms had shifted from a normal daytime schedule to a schedule more closely resembling the nighttime schedule that a shift worker might follow. In other words, instead of being awake during the day and sleeping at night, they were sleeping during the day and were awake at night. However, because the study subjects were not exposed to any windows and no other "cues" to tell them what time it actually was, they were unaware that this shift or "circadian misalignment" had taken place.
What did you learn?
We kept careful measurements of subjects' blood pressure, blood glucose and sleep quality. We also routinely measured hormone levels, including leptin, insulin and the "stress hormone" cortisol. We discovered when the subjects' sleep-wake cycles had been shifted by approximately 12 hours, their hormone levels showed the largest deviations from normal: Leptin levels dropped significantly, by approximately 20 percent; cortisol levels were completely reversed; and insulin levels were elevated by approximately 20 percent. Importantly, sleep efficiency was also reduced by approximately 20 percent.
How might these findings translate to a person's health?
The greatly reduced leptin levels can lead to increased appetite and decreased activity, putting individuals at greater risk for obesity. This, in association with completely reversed cortisol levels, may cause increased insulin resistance and symptoms of the metabolic syndrome. Most troubling, three of our study subjects - who had no previous history of diabetes - actually finished the study with glucose measurements typical of patients with "pre-diabetes." On average, we observed increased blood sugar and blood pressure levels, which, if sustained, can lead to increased risk for cardiovascular disease, including heart attacks.
Taken together, all of these findings strongly suggest that "circadian misalignment" can lead to metabolic and cardiac disorders.
How do these results fit in with other leptin research you've conducted and what are your next steps in studying leptin-deficiency states?
This condition of "circadian misalignment" is now becoming part of a group of low-leptin disorders that are closely associated with a number of important disease states. All of these relative leptin-deficiency states are helping us to understand the underlying mechanisms leading to disease and leading us to the conclusion that if leptin deficiency cannot be prevented by lifestyle modifications, replacement treatment may be necessary to maintain good health.
Going forward, we need to better identify the normal ranges for leptin levels in both men and women. To accomplish this, we will continue to pursue clinical research and will work to enroll patients for participation in clinical trials in order to learn more about this important hormone and the role it plays to our health.
From the Proceedings of the National Academy of Sciences (PNAS), Advance On-line Publication, March 2, 2009. "Metabolic and cardiovascular consequences of circadian misalignment" by Frank A.J.L. Scheer, Michael F. Hilton, Christos S. Mantzoros and Steven A. Shea.
To learn more about work in the Mantzoros laboratory,