According to two studies, tampering with the circadian clocks that keep the body and its cells in sync with the 24-hour day-night cycle is a major factor in weight gain.
According to one study published on June 27 in Cell Reports, stress generated by repeatedly injecting glucocorticoid stress hormones and disrupting the usual daily cycle of release generates a transient defensive mechanism in mice. This process promotes fat cell development and insulin production while decreasing blood sugar and fat levels in the blood and liver. The second study, published on August 8 in the Proceedings of the National Academies of Sciences, indicates that during the rest period of mice, fat cell precursors commit to becoming fat cells. According to the findings, stress and other variables that disrupt the body's "clocks" may lead to weight growth and propose novel therapeutic techniques for obesity.
"A lot of forces are fighting against a healthy metabolism when we are out of circadian rhythm," said Dr. Mary Teruel, associate professor of biochemistry and member of Weill Cornell Medicine's Gale and Ira Drukier Institute for Children's Health. "The more we learn, the more likely it is that we will be able to do something about it."
Dr. Teruel and colleagues conducted the first investigation to imitate the disruptive effects that illnesses such as Cushing's disease or chronic stress have on the normal daily swings in glucocorticoids, a class of stress-related hormones. To accomplish this, they implanted pellets that produced glucocorticoids at a steady rate under the skin of mice for 21 days and compared them to normal mice with normal daily fluctuations. The amount of brown and white fat in the mice given glucocorticoid pellets doubled in 21 days, and insulin levels in their bodies spiked, despite the mice eating the same healthy food as the control mice.
"It has a tremendous effect if you stress the animals at the wrong time," Dr. Teruel added. "The mice do not eat differently, but a significant change in metabolism promotes weight gain."
Surprisingly, these metabolic disturbances appeared to have a "protective impact" by maintaining low blood sugar levels and preventing fat accumulation in the blood or liver. When the pellets were removed, the metabolic alterations were promptly restored.
"It demonstrates that animals can tolerate persistent stress for a period of time," she said.
In the second study, Dr. Teruel and her colleagues attached a red fluorescent protein to a protein that regulates the expression of important circadian clock genes and a yellow fluorescent protein to a protein that regulates fat cell production, peroxisome proliferator activated receptor gamma (PPARG). They employed these two fluorescent markers to track PPARG and circadian gene expression in mouse fat cell progenitors on a daily basis. They discovered that a circadian protein called CCAAT enhancer binding protein alpha (CEBPA) induces a rapid surge in PPARG production during the day's rest phase. When PPARG levels reach a particular level, the precursor cells commit to becoming fat cells, which takes a few days.
"Over the course of four hours, the decision to become a fat cell is made quickly. It's like flipping a switch "She stated. "It only occurs at particular times of the
Dr. Teruel and her colleagues are now investigating why disrupting glucocorticoid diurnal cycles causes transient protective metabolic alterations. They also want to know if persistent stress or a high-fat diet causes these alterations to be permanent. The findings of these trials could help decide how long it is safe to use glucocorticoid medications to treat illnesses such as asthma.
The discovery could also lead to the development of medications that assist people with obesity reset their circadian rhythms as an alternative to more intrusive therapies like bariatric surgery. To avoid excess fat buildup, medicines targeting the 4-hour window when fat cell precursors commit to becoming fat cells could be an option.
Dr. Teruel and her colleagues feel that understanding how to synchronise the body's cellular and master circadian clocks will also be critical.
"Every cell in our body, including fat cells, has an intrinsic cell clock, and we have a master clock in our brain that controls hormone output," she explained. "We're attempting to figure out how they interact and how we can coordinate them."
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Stefan Tholen, Roma Patel, Agnieszka Agas, Kyle M. Kovary, Atefeh Rabiee, Hayley T. Nicholls, Ewa Bielczyk-Maczyńska, Wenting Yang, Fredric B. Kraemer, Mary N. Teruel. Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy. Cell Reports, 2022; 39 (13): 111018 DOI: 10.1016/j.celrep.2022.111018
Zhi-Bo Zhang, Joydeb Sinha, Zahra Bahrami-Nejad, Mary N. Teruel. The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment. Proceedings of the National Academy of Sciences, 2022; 119 (33) DOI: 10.1073/pnas.2204470119