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Synch Mealtimes With the Circadian Clock, Suggests New Mouse Study

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A new study in mice has found that restricting eating to the active period of the daily circadian rhythm limits weight gain and improves metabolic health using increased heat-generating creatine metabolism in fat cells. The study is published in Science.

Understanding the body clock

Fat cells (adipocytes) utilize energy from excess calories consumed in our diet. White adipose tissue stores energy, while brown adipose tissue “burns” excess energy, generating heat and maintaining body temperature through a process called thermogenesis.

The circadian clock regulates the body’s biochemical processes, setting an internal near-24-hour cycle that controls many background processes, such as the sleep–wake cycle, hormonal activity and body temperature. This internal clock is reset every day by the cycle of light and dark from the sun – and humans can even use supplements of the sleep hormone melatonin to adjust its timings.

Time-restricted feeding (TRF) can limit weight gain and improve metabolic health in both rodents and humans. Additionally, studies in mice have shown that mistiming feeding with the inactive phase of the circadian clock (which, for rodents, is during the day) can contribute to weight gain.

What is time-restricted feeding?

Time-restricted feeding (TRF) means that the window of time in which food is consumed is restricted, with the rest of the time spent fasting, and no other changes made to the number of calories consumed or the composition of the diet.

However, we don’t yet understand the cellular mechanisms that lead to the effects of TRF. In the current study, the researchers investigated the impact of TRF in mice given a high-fat diet during the active and inactive phases of their circadian rhythm.

Mistimed feeding affects metabolism

Results from the TRF experiments showed that mice fed only during the inactive (light) period of their circadian cycle for one week gained significantly more weight than mice fed only during the active (dark) phase, despite similar food intake and digestive efficiency.

The researchers found that increased thermogenesis in fat cells contributes – at least partly – to the apparent benefits of dark-restricted feeding in mice.

Thermogenesis is largely regulated by a protein called uncoupling protein 1 (UCP1), which rewires the production of adenosine triphosphate (ATP), the energy currency of the cell. However, thermogenesis can also occur without UCP1, using a “futile creatine cycle” – a metabolic pathway that was increased in the mice in the dark-restricted feeding group.

On the other hand, light-restricted feeding impaired thermogenesis and futile creatine cycling, making these mice more susceptible to diet-induced weight gain.

Additionally, zinc finger protein 423 (ZFP423) blocks genes that control thermogenesis. Genetically engineering mice that lacked ZFP423 in their fat cells also had increased thermogenesis, protecting them from weight gain during mistimed feeding.

“We discovered that there are daily circadian rhythms of creatine metabolism in fat cells,” explained Dr. Chelsea Hepler, lead author of the study and postdoctoral fellow at Northwestern University. “When mice eat only during their normal active period, they expend more energy through elevated creatine futile cycling. However, when food is provided only during the time when mice are normally sleeping, the mice have reduced energy expenditure since the timing of their food intake is misaligned with creatine metabolism.”

“Our findings reveal that aligning food intake with circadian rhythms in adipocyte creatine thermogenesis improves metabolic health,” Hepler summarized.

Do TRF benefits extend to humans?

Overall, these results broaden our understanding of the effects of TRF, suggesting the promise of this approach for weight loss or improving metabolic health. The researchers also suggest that frequent changes to the circadian clock and feeding schedules in people could worsen metabolic diseases, particularly for shift workers or those experiencing sleep loss, though further work is required to validate these findings in humans.

“The study was only performed in mice, though prior work by other labs showed that human adipocytes are capable of utilizing creatine to expend energy,” Hepler elaborated. “It will be critical to identify whether a similar pathway is elevated in humans during time-restricted feeding.”

Reference: Hepler C, Weidemann BJ, Waldeck NJ, et al. Time-restricted feeding mitigates obesity through adipocyte thermogenesis. Science. 2022;378(6617):276-284. doi: 10.1126/science.abl8007

Dr. Chelsea Hepler was speaking to Sarah Whelan, Science Writer for Technology Networks.