Does Circadian Cycle Play a Role in Weight Gain?

Disruption of circadian clocks plays a vital role in weight gain, suggested two studies conducted by researchers at Weill Cornell Medicine. The circadian clocks keep the body and its cells synchronised to the 24-hour day-night cycle. According to a study that was published in June 2022 in Cell Reports, mice develop a transient defence mechanism in response to stress brought on by the prolonged administration of glucocorticoid stress hormones and disruption of the hormones’ regular daily cycle of release. This process lowers excessive blood sugar and fat levels in the bloodstream and liver while increasing insulin synthesis and fat cell proliferation.

The second study, which was released in early August 2022 in the Proceedings of the National Academies of Sciences, demonstrates that during the rest period of mice, fat cell precursors commit to developing into fat cells. The discoveries offer novel therapeutic options for obesity and imply that stress and other variables that disrupt the body's ‘clocks’' may contribute to weight gain.

“A lot of forces are working against a healthy metabolism when we are out of circadian rhythm. The more we understand, the more likely we will be able to do something about it,” said the senior author of both studies Dr Mary Teruel, associate professor of biochemistry and a member of the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.

As part of the initial investigation, researchers mimicked how glucocorticoids, a class of stress-related hormones, are affected by illnesses like Cushing’s disease or long-term stress. To do this, they implanted mice with pellets beneath their skin that released glucocorticoids continuously for 21 days while comparing them to control mice who experienced daily changes naturally. Even though the mice consumed the same nutritious meal as the normal mice, their brown and white fat doubled within 21 days. Also, their insulin levels shot through the roof.

“If you stress the animals at the wrong time, it has a dramatic effect. The mice aren't eating differently, but a big shift in metabolism causes weight gain," said Dr Teruel.

Surprisingly, these metabolic disturbances seemed to have a protective impact by preventing fat from accumulating in the blood or liver and maintaining low blood sugar levels. These metabolic modifications got undone when the pellets were removed.

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“It shows the animals can cope with chronic stress for a while,” said Dr Teruel.

In the second study, researchers fused a yellow fluorescent protein to peroxisome proliferator-activated receptor gamma (PPARG), a protein that controls the production of fat cells, and a red fluorescent protein to a protein that regulates the expression of crucial circadian clock genes. These two fluorescent markers were utilised to track PPARG and circadian gene expression variations throughout the day in mouse fat cell progenitors. They discovered a circadian protein called CCAAT enhancer binding protein alpha (CEBPA) causes a sharp surge in the production of PPARG during the day's rest phase. The precursor cells commit to becoming fat cells after PPARG levels cross a particular threshold, which takes a few days to accomplish.

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“The decision to become a fat cell happens rapidly over four hours. It is like a switch. It only happens at a certain time of day,” said Dr Teruel.

Researchers are attempting to determine why glucocorticoid disruption causes momentary protective metabolic alterations. They also want to know if these changes are made permanent by ongoing stress or a high-fat diet. These findings may help to establish how long it is safe to administer glucocorticoids to people for ailments like asthma.

As an alternative to more invasive therapies like bariatric surgery, the research may also help the development of medications that assist obese individuals in resetting their circadian cycles. Therapies that target the four-hour window when fat cell precursors commit to becoming fat cells may be another option for preventing the build-up of extra fat.

“Every cell in our body has an intrinsic cell clock, just like the fat cells, and we have a master clock in our brain, which controls hormone secretion. We are trying to understand how they work together and how we can coordinate them,” said Dr Teruel.

Source-Medindia