Disrupting normal hormone cycle spurs fat cells

At a Glance

  • In mice, interfering with the natural cycle of a certain hormone spurs development of more fat cells.
  • This finding may help explain why stress and conditions associated with abnormal steroid hormone levels can cause obesity.
Microscope image of fat precursor cells.
The fat precursor cells that were used to test the effects of steroid hormones on a molecular and cellular level. Z. Bahrami-Nejad et al., Cell Metabolism

Your body has a natural, daily rhythm. Certain needs—to sleep, wake up, eat, and go to the bathroom every day—are patterned around a repeating 24-hour cycle. Hormones rise and fall at certain times of the day to prompt the body to do these things at the right time. When you go against these natural  “circadian” rhythms—by forcing yourself to stay up too late, for example—your health may suffer. Disrupted circadian rhythms have been linked to obesity, sleep disorders, depression, and other health problems.

Previous studies have shown that steroid hormones known as glucocorticoid hormones, which drive adipocyte (fat cell) production from precursors, are secreted on a 12-hour cycle. Disrupting this cycle is linked to obesity. In addition to this natural daily rhythm, your body also secretes glucocorticoids during stressful situations. Some people have diseases, such as Cushing’s disorder, or steroid treatments that result in higher than normal levels of these hormones in the body. These conditions are also linked to obesity.

To find out why disruptions in glucocorticoid cycles seem to result in the accumulation of fat cells, a research team led by Dr. Mary Teruel of Stanford University examined the impact of the timing and dose of hormones on mice. The work, which was funded by several NIH components, was published on April 3, 2018, in Cell Metabolism.

The research team kept mice on a schedule of 12 hours of light, from 7 a.m. to 7 p.m. (when the body’s steroid hormone levels peak), and 12 hours of darkness (when levels fall). They gave eight-week-old male mice a constant dose of steroid hormone or placebo. The team found that the amount of fat doubled in mice whose concentration of hormone remained constant all the time for 21 days, compared to mice who had normal 12-hour fluctuations of light and darkness.

Next, they confirmed that it was the 12-hour “off” period of darkness that was important by giving steroid hormones to one group of mice every day at 5 p.m. for 21 days to create a 40-fold increase in peak hormone levels. There was no difference in fat between mice receiving a placebo or this high dose of hormone during the light period.

The research team also analyzed precursor fat cells on a molecular level to study the effects of the daily glucocorticoid cycle. They found that if the steroid hormone is given constantly (no “off” cycle) over 21 days, a protein known as PPARG builds up and pushes more precursor cells into becoming fat cells. Normally, the PPARG level is reset each day during the “off” period and fat cells don’t develop. The findings show that if the “off” cycle lasts less than a normal 12-hour circadian cycle, a switch is flipped, and precursor cells become fat cells.

“Now we know the circadian code that controls the switch, and we’ve identified key molecules that are involved,” Teruel says. “Our results suggest that even if you get significantly stressed or treat your rheumatoid arthritis with glucocorticoids, you won’t gain weight, as long as stress or glucocorticoid treatment happens only during the day. But if you experience chronic, continuous stress or take glucocorticoids at night, the resulting loss of normal circadian glucocorticoid oscillations could result in significant weight gain.”

—by Geri Piazza

Related Links

References: A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. Bahrami-Nejad Z, Zhao ML, Tholen S, Hunerdosse D, Tkach KE, van Schie S, Chung M, Teruel MN. Cell Metab. 2018 Apr 3;27(4):854-868.e8. doi: 10.1016/j.cmet.2018.03.012. PMID: 29617644.

Funding: NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Human Genome Research Institute (NHGRI); Stanford BioX Seed Grant; American Heart Association; and the DFG, German Research Foundation.

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