Disrupting the circadian clocks that keep the body and its cells engaged in the 24-hour day-night cycle plays a critical role in weight gain, according to two studies by Weill Cornell Medicine researchers.
A study, published June 27 in Cell Reports, found that stress caused by chronic administration of glucocorticoid stress hormones and disruption of the normal daily cycle of release triggers a temporary protective mechanism in mice. This mechanism stimulates fat cell growth and insulin production while reducing excess blood sugar and fat levels in the blood and liver. The second study, published August 8 in the Proceedings of the National Academies of Sciences, shows that fat cell precursors engage in becoming fat cells during the resting period of mice. Studies suggest that stress and other factors that disrupt the body’s “clocks” may contribute to weight gain and suggest new approaches to treating obesity.
“Many forces act against healthy metabolism when we are out of circadian rhythm,” explained lead author of both studies, Dr. Mary Teruel, associate professor of biochemistry and fellow at the Gale and Ira Drukier Institute for Health. children at Weill Cornell Medicine. “The more we understand, the more we will be able to do something about it.”
In the first study, Dr. Teruel and his colleagues mimicked the disruptive effects of conditions such as Cushing’s disease or chronic stress on the usual daily fluctuations of glucocorticoids, a class of stress-related hormones. To do this, they implanted pellets that released glucocorticoids at a constant rate for 21 days under the skin of mice and compared them to normal mice that have normal daily fluctuations. The amount of brown and white fat in the mice with the glucocorticoid pellets doubled in 21 days, and insulin levels in their bodies skyrocketed even though the mice still ate the same healthy diet as normal mice.
“If you stress the animals at the wrong time, it has a dramatic effect,” Dr Teruel said. “Mice don’t eat differently, but a big change in metabolism leads to weight gain.”
Surprisingly, these metabolic disturbances appeared to have a “protective effect” by keeping blood sugar levels low and preventing fats from building up in the blood or liver. When they removed the pellets, the metabolic changes quickly reversed.
“It shows that animals can cope with chronic stress for quite some time,” she said.
In the second study, Dr. Teruel and colleagues attached a red fluorescent protein to a protein that controls the expression of important circadian clock genes and a yellow fluorescent protein to the peroxisome proliferator-activated receptor gamma (PPARG ), a protein that regulates the production of fat cells. They used these two fluorescent markers to monitor daily fluctuations in PPARG and circadian gene expression in mouse fat cell precursors. During the rest period of the day, they discovered that a circadian protein called CCAAT enhancer binding protein alpha (CEBPA) causes a rapid increase in the production of PPARG. Once PPARG levels reach a certain threshold, the precursor cells commit to becoming fat cells, a process that takes a few days.
“The decision to become a fat cell is made quickly in 4 hours. It’s like a switch,” she said. “It only happens at a certain time of the day.”
Dr. Teruel and his colleagues are now working to understand why disruption of daily glucocorticoid rhythms triggers temporary protective metabolic changes. They also want to know if prolonged stress or a high-fat diet makes these changes permanent. The results of these studies could help determine how long it is safe to treat people with glucocorticoid medications for conditions like asthma.
The research could also lead to the development of drugs that help reset circadian rhythms in obese people as an alternative to more invasive treatments like bariatric surgery. Another possibility could be therapies targeting the 4-hour window when fat cell precursors commit to becoming fat cells to prevent excess fat accumulation.
Dr. Teruel and his colleagues also believe that learning to synchronize the body’s cellular and master circadian clocks will be essential.
“Every cell in our body has an intrinsic cell clock, just like fat cells, and we have a master clock in our brain, which controls hormone secretion,” she said. “We’re trying to figure out how they work together and how we can coordinate them.”