Circadian clocks involve primarily in fat cell growth

According to two studies conducted by researchers at Weill Cornell Medicine, the circadian clocks that keep the body and its cells synchronized to the 24-hour day-night cycle are severely disrupted.

According to a study that was published on June 27^th, 2022, in Cell Reports, mice develop a transient defense 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 on August 8^th, 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.”

Dr Mary Teruel, Study Senior Author and Associate Professor, Biochemistry, Weill Cornell Medicine

Teruel was also a member of the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.

In the initial investigation, Dr Teruel and associates imitated the disruptions that illnesses like Cushing’s disease or long-term stress have on the regular daily swings of glucocorticoids, a class of stress-related hormones.

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 experience daily changes normally. Even though the mice continued to consume the same nutritious meal as the normal mice, their levels of brown and white fat doubled within 21 days and 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,” Dr Teruel said.

Interestingly, these metabolic disturbances appeared to have a “protective effect” by maintaining stable blood sugar levels and preventing fat from building up in the liver or circulation. When the pellets were taken away, the metabolic modifications were immediately undone.

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

In the second study, Dr. Teruel and her coworkers fused a yellow fluorescent protein to peroxisome proliferator-activated receptor gamma (PPARG), a protein that leads to 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 utilized 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.

“The decision to become a fat cell happens rapidly over 4 hours. It is like a switch. It only happens at a certain time of day,” she said.

Currently, Dr Teruel and her associates 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 studies’ findings may be used to establish how long it is safe to administer glucocorticoids to people for ailments like asthma.

As an alternative to more intrusive therapies like bariatric surgery, the research may also result in the creation of medications that assist obese individuals in resetting their circadian cycles. Therapies that target the 4-hour window when fat cell precursors commit to becoming fat cells may be another option for preventing the build-up of extra fat.

It will also be crucial, in the opinion of Dr Teruel and her associates, to learn how to synchronize the master and cellular circadian clocks of the body.

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.”

Dr Mary Teruel, Study Senior Author and Associate Professor, Biochemistry, Weill Cornell Medicine