“If you stress the animals at the wrong time, it has a dramatic effect,” Dr. Teruel said. “The mice aren’t eating differently, but a big shift in metabolism causes weight gain.”
Surprisingly, these metabolic disruptions seemed to have a “protective effect” by keeping blood sugar levels low and preventing fat from accumulating in the blood or liver. When they removed the pellets, the metabolic changes quickly reversed.
“It shows the animals can cope with chronic stress for a while,” she said.
In the second study, Dr Teruel and her colleagues attached a red fluorescent protein to a protein that controls the expression of important circadian clock genes and a yellow fluorescent protein to peroxisome proliferator activated receptor gamma (PPARG), a protein that regulates fat cell production. They used these two fluorescent markers to monitor the daily fluctuations of PPARG and circadian gene expression in mouse fat cell precursors. During the rest period of the day, they found 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 to complete.
“The decision to become a fat cell happens rapidly over 4 hours. It is like a switch,” she said. “It only happens at a certain time of day.”
Dr. Teruel and her colleagues are now working to understand why disturbing the daily rhythms of glucocorticoids triggers temporary protective metabolic changes. They also want to learn whether 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 individuals with glucocorticoid drugs for conditions like asthma.
The research might also lead to the development of drugs that help reset circadian rhythms in people with obesity as an alternative to more invasive treatments like bariatric surgery. Another possibility might be therapies targeting the 4-hour window when fat cell precursors commit to becoming fat cells to prevent excess fat accumulation.
Dr. Teruel and her colleagues also believe learning how 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 the fat cells, and we have a master clock in our brain, which controls hormone secretion,” she said. “We are trying to understand how they work together and how we can coordinate them.”
