Intermittent fasting has become a popular strategy for boosting health and metabolism, but a new study suggests that its benefits may be blunted by body fat, thanks to a hidden disruption in the liver’s ability to adapt to starvation.
Researchers monitored changes in the livers of healthy mice and obese mice lacking leptin, a hormone that regulates appetite, during periods of food deprivation. Intermittent fasting involves prolonged periods of calorie restriction followed by windows of normal eating.
Although both groups of mice maintained a similar metabolic network — the system of molecules in the liver that work together to manage energy — they found a crucial difference in timing.
“In a healthy liver, energy-related molecules such as adenosine triphosphate (ATP) and adenosine monophosphate (AMP) respond rapidly to starvation and regulate numerous metabolic reactions,” co-lead author Prof Shinya Kuroda told BBC Science Focus.
“This process appears to be disrupted in obesity.”
In other words, in healthy mice, energy-related molecules such as ATP and AMP acted as central hubs, rapidly orchestrating metabolic changes to conserve and redistribute energy. In obese mice, however, these molecules were unresponsive, leading to a sluggish and disorganised response to starvation.
When ATP and AMP react quickly to a lack of food, they help the liver switch from storing energy to burning it. It’s this shift that’s thought to drive many of intermittent fasting’s benefits, such as weight loss and improved blood sugar control.
By combining structural and temporal metabolic analysis, the team uncovered how obesity introduces a kind of metabolic ‘jet lag’, disrupting when – not just how – key molecular events unfold.
“Our findings have potential implications for enhancing the therapeutic effects of intermittent fasting in humans,” Kuroda said.
“Next, we must identify blood-based biomarkers that are easy to monitor in humans,” Kuroda said. “Finally, a clinical study is required to validate our findings. It is a long journey, but a journey of a thousand miles begins with a single step.”
The study was published in Science Signaling.
About our expert
Shinya Kuroda is a professor in the School of Science at the University of Tokyo, in Japan, specialising in systems biology. His research has been published in notable journals such as Cell, The Journal of Biological Chemistry and Nature Cell Biology.
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