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The findings open new avenues for exploring how other environmental signals influence cellular behavior.
By Pesach Benson, TPS
Findings announced by Israeli researchers on Monday may reshape science’s understanding of how fasting impacts metabolic health and open new doors for personalized nutrition plans and sustainable weight control.
Fasting has long been an integral part of human culture, practiced for religious, spiritual, and health reasons. In recent years, fasting has gained popularity as a modern health strategy, with intermittent fasting, prolonged fasting, and time-restricted eating touted for benefits like improved metabolic health, weight management, and even longevity.
However, while much is known about the physiological effects of fasting, scientists at Jerusalem’s Hebrew University uncovered how the liver adapts to repeated fasting at the molecular level, introducing the concept of what the researchers call “metabolic memory.”
The research team, led by Dr. Ido Goldstein, examined how the liver adapts to repeated fasting uncovered a cellular memory mechanism that enhances its metabolic response.
The study, recently published in the peer-reviewed Nucleic Acids Research explored how alternate-day fasting (ADF) “sensitizes” key genes and liver enhancers.
It found that this metabolic “memory” is driven by chromatin — a complex of DNA and protein — and the dynamics of transcription factor proteins.
The scientists studied the impact of ADF on liver function in mice, revealing significant changes in how the liver responds to repeated fasting.
Mice subjected to ADF displayed enhanced gene activation and a heightened ability to produce ketone bodies, which serve as an energy source during fasting.
These adaptations were absent in mice fasting for the first time, highlighting the liver’s ability to adapt to recurring fasting states.
The researchers identified a process called “sensitization,” where key genes involved in ketogenesis — the production of ketone bodies — became more responsive after repeated fasting.
This phenomenon was linked to changes in the liver’s chromatin landscape. Enhancers, which regulate gene expression, became “primed” for stronger activation following prior fasting experiences.
The transcription factor PPARα was found to play a crucial role in this process, as the adaptive response was absent in mice lacking PPARα in liver cells.
The study demonstrated that the liver’s adaptation to fasting is specific to fasting states and does not affect feeding periods.
After just one week of ADF, mice exhibited enhanced ketone production during subsequent fasting bouts, with gene expression and ketone levels returning to baseline during feeding periods.
Interestingly, these metabolic benefits occurred independently of changes in calorie intake or body weight, emphasizing the liver’s dynamic response to fasting rather than overall dietary intake.
“Our study highlights how the liver adapts to repeated fasting through a memory-like mechanism that prepares it for future fasting bouts,” Goldstein explained.
“This enhancer sensitization process underscores the liver’s remarkable ability to dynamically respond to recurring nutritional states.”
The findings open new avenues for exploring how other environmental signals influence cellular behavior.
For example, intermittent fasting regimens could be customized to enhance metabolic health for specific populations, such as those with metabolic syndrome, obesity, or type 2 diabetes.
The findings also show fasting’s potential as a strategy for managing metabolic health, particularly in improving liver adaptability to address conditions like non-alcoholic fatty liver disease.
Enhanced ketone production and lipid metabolism may lower risk factors for heart disease, such as high cholesterol and triglycerides.
Additionally, fasting’s ability to boost insulin sensitivity and metabolic flexibility, making it a potential tool for managing diabetes.
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