Stress can disrupt circadian rhythms and lead to weight gain

  • Most human cells, including fat cells, are driven by their own circadian clocks that coordinate metabolism with the daily rest-wake cycle.
  • Two recent studies from Weill Cornell Medicine found that stress and other factors can disrupt these “clocks,” contributing to weight gain.
  • The findings could pave the way for innovative approaches to treating obesity.

Scientists at Weill Cornell Medicine in New York say that stress-induced circadian clock disruptions can influence weight gain.

A study published in June showed that mice with artificially increased stress levels and interrupted hormone releases experienced increased fat cell growth. Its results appear in Cell reports.

The second study, published in August, found that fat cell precursors only commit to becoming fat cells within hours overnight. This work appears in the Proceedings of the National Academies of Sciences (PNAS).

Mary Teruel, PhD, associate professor of biochemistry at Weill Cornell Medicine, was lead author on both studies.

“Many forces act against healthy metabolism when we are out of circadian rhythm,” Dr. Teruel said in a press release. “The more we understand, the more we will be able to do something about it.”

In the Cell reports study, Dr. Teruel and his team implanted pellets of glucocorticoids, a type of stress-related hormone, in mice. It was to mimic the effects of chronic stress or Cushing’s disease.

Cushing’s disease triggers high levels of cortisol, the body’s stress hormone.

The pellets released glucocorticoids under the mice’s skin at a constant rate for three weeks. The researchers also observed control mice showing typical daily fluctuations in stress hormones.

Although all the mice ate the same healthy diet, the mice on the pellets ended up weighing more than 9% more than the control mice.

The researchers observed whether the weight gain came from fat expansion and found that the brown and white fat of the pellet mice more than doubled. Their insulin levels also increased.

To the team’s surprise, the metabolic disturbances kept blood sugar levels low. In addition, the disturbances prevented fat from accumulating in the blood or liver.

When the researchers removed the pellets, these changes immediately reversed.

Dr. Teruel explained to DTM: “We saw that in our paper, basically, once we stopped flattening corticosteroids, [the mice] started backing up [the fat mass gain] and the hyperinsulinemia disappeared so that the increase in insulin seemed to cause the fat mass gains which disappeared when the rhythm was restored.

She added that this study indicates that chronic stress can make weight gain more likely, even with a healthy, low-fat diet.

“If you stress the animals at the wrong time, it has a dramatic effect. Mice don’t eat differently, but a big change in metabolism leads to weight gain,” Dr. Teruel said in the statement.

Dr. Teruel’s research team hopes their findings will lead to the development of drugs that could help reset circadian rhythms to help obese people.

“We don’t know enough [yet]but one would think that cortisol receptor antagonists or […] things that restore cortisol rhythms would probably help a lot.

– Dr. Mary Teruel, PhD, associate professor of biochemistry at Weill Cornell Medicine and senior author of both studies

Experts understand that defects in circadian clock genes can alter cell differentiation in fat, immune, skin and muscle cells.

The PNAS One study found that while differentiation occurs within days, differentiation engagement occurs within hours. The results also show that the “daily bursts” of cell differentiation seem to be limited to the evening phases, when people are normally resting.

“The decision to become a fat cell is made quickly in 4 hours. It’s like a switch,” said Dr. Teruel.

Medical News Today discussed it with Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California.

Dr. Ali explained how fat cells are formed: “Fat cells are formed from [an] adipocyte progenitor cell or a type of cell that has not differentiated into its final form. The form it takes [to become] a fat cell depends on the hormonal and chemical stimulation it receives.

In the study, Dr. Teruel and his partners used fluorescent markers to observe daily fluctuations in fat cell production.

The researchers attached a red fluorescent protein to a protein that regulates circadian clock genes. They also attached a yellow fluorescent protein to the peroxisome proliferator-activated receptor gamma (PPARG), a protein that controls the production of fat cells.

They found that during the resting period of the day, a certain circadian protein – CCAAT enhancer binding protein alpha – induces a rapid increase in the protein that regulates fat cell production.

The researchers also found that when PPARG levels reach a certain threshold, individual fat precursor cells “irreversibly commit to differentiating within just a few hours, which is much faster than the resting phase and the process global differentiation over several days”.

Dr. Teruel and his team believe that working with this time window “may open up therapeutic strategies for using timed treatment versus the [circadian] clock to promote tissue regeneration.

Dr Ali said: “These studies are interesting in that they show that the timing and duration of stimulation affects the formation and growth of fat cells. The implications of this are that if we can find a way to safely influence the cell to grow or not grow, it may affect obesity in humans.

However, he thinks more research is needed to make the results of the studies applicable to humans.

Dr. Teruel said DTM that she and her co-writers were “just trying to work out basic mechanics […] Right now we have to show that it’s really a mechanism that happens […]”

The researchers plan to replicate the studies with people. “We are looking at protein ribbons and humans using saliva samples,” Dr. Teruel shared with DTM. “We plan to do these kinds of experiments.”

Their main goal, she said, is “to find ways to restore the circadian rhythm [rhythms].”

Dr. Teruel mentioned that currently known strategies, such as meditation and regular dark sleeping, can help.

She expressed the hope that “there might be pharmacological means [to] solve this problem in the future”.