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September 14, 2022

Disruptions in Circadian Clock Contributes to Fat Cell Growth, New Studies Find

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Two recent studies conducted at Weill Cornell suggest that there’s more to gaining weight than diet. Chronic stress and disruptions in one’s circadian clocks may play a key role in fat cell growth.

The first study, published in Cell Reports this past June, researched the effect that chronic stress and Cushing’s disease — a disease that stimulates excess production of the stress hormone cortisol — have on weight gain and obesity, ultimately finding it plays a key role.

Glucocorticoids, stress hormones in our bodies released in response to cortisol, normally kick-up around 7 a.m., and will spike and drop throughout the day until dropping at night. These oscillations glucocorticoid levels are mediated by the body’s circadian clock.

Cushing’s disease, as well as chronic stress, may result in the flattening of these circadian oscillations, causing these spikes in glucocorticoid to decrease. This normally occurs when prolonged stress stimulates constant release of glucocorticoids instead of its normal, biological cycle..

“If you don’t sleep [properly] at night, the next day you will have increased cortisol levels at night,” said Prof. Mary Teruel, biochemistry. “[B]ut there is a compensation that will bring down peak levels so the total amount of cortisol in the bloodstream is constant.” 

To test the effects of this circadian disruption, Teruel and her colleagues replicated the stress that humans may face when sustaining work-life imbalances in mice. This was done by implanting mice with corticosterone pellets to simulate high levels of cortisol constantly. By prolonging glucocorticoid levels in the mice, researchers found that insulin levels and the amount of fatty tissue rose, ultimately resulting in obesity and fat cell growth. 

When circadian rhythms were restored however, the effects were reversed.

Fat cell growth did not vary due to diet or the amount of glucocorticoids. The mice all got the same amount of glucocorticoids, but some got it at the wrong time causing their fat mass to double. Even with a really healthy diet. This suggests that the fat cell growth is independent of diet.

The importance of the body’s cycles of regulation is further emphasized in the second study, published in Proceedings of the National Academy of Sciences this past August. This study follows the timing of fat cell differentiation in response to a cell’s circadian clock. 

Using live cell imaging, and fluorescent markers, fluctuations of peroxisome proliferator- activated receptor gamma — a protein mediating fat cell production — and circadian gene expression were monitored. Preadipocytes have a circuit based on PPARG. If you stay on rhythms, PPARG will not reach the threshold to become a fat cell, however, if you give continuous stimuli, it will become a fat cell. Once this threshold to become a fat cell is reached, it is irreversible. 

It takes an extended period of time to become a fat cell, but the decision to become one is very rapid, occurring in a window of around 4 hours.  

“Cells are only committing in the rest phase, and only make this 4 hour decision [to become a fat cell] based on the feedback loops that drive it,” Teruel said. 

Provided that the cells commit to becoming fat cells during the rest phase, diet during this phase may result in weight gain as consuming a high fat diet during a rest phase will result in you becoming much more obese than if you were to eat the same thing during the day phase.