A new study reveals how repeated fasting enhances the liver’s ability to adapt through a cellular memory mechanism. The research shows that alternate-day fasting “sensitizes” key genes and liver enhancers, boosting ketogenesis during subsequent fasting bouts. This process, driven by the transcription factor PPARα, highlights how the body adjusts to recurring nutritional challenges. These findings provide fresh insights into the metabolic benefits of fasting and its potential applications in health and dietary science.

Fasting is an integral part of everyday life for millions of people worldwide, often practiced for religious or spiritual purposes. Observances such as Ramadan in Islam, Yom Kippur in Judaism, Lent in Christianity, and fasting rituals in Hinduism and Buddhism are deeply rooted in tradition and faith. These practices often involve repeated fasting periods, raising intriguing questions about how the body adapts to such recurring nutritional states.

In recent years, fasting has also become fashionable beyond its religious and cultural roots, embraced as a tool for improving health and promoting weight loss. Intermittent fasting, prolonged fasting, and time-restricted eating are increasingly popular, with advocates claiming benefits such as enhanced metabolic health, weight management, and even longevity. This trend underscores the importance of understanding the physiological mechanisms underlying fasting, both in traditional contexts and as a modern lifestyle choice.

A new study published at Nucleic Acids Research led by Dr. Ido Goldstein from the Institute of Biochemistry, Food Science, and Nutrition at the Robert H. Smith Faculty of Agriculture, Food and Environment at the Hebrew University of Jerusalem reveals how repeated fasting triggers a cellular memory mechanism in the liver, enhancing its response to future fasting events. The research uncovers a fascinating link between alternate-day fasting (ADF) and the liver’s ability to adapt through heightened gene activation and production of a fuel termed ketone bodies, offering new insights into metabolic regulation.

Fasting induces metabolic changes in mammals, enabling the production of glucose and ketone bodies for energy during periods of food scarcity. This process is driven by transcriptional changes in the liver (i.e. changes in the expression of genes). Dr. Goldstein’s team investigated how recurring fasting events, such as those experienced during ADF, influence this transcriptional program. Their findings revealed that mice undergoing ADF responded significantly differently to subsequent fasting bouts compared to mice fasting for the first time.

The study identified a phenomenon termed “sensitization,” where key genes responsible for ketogenesis (the production of ketone bodies) were more strongly activated following ADF. This effect was linked to changes in the liver’s chromatin landscape, with enhancers—genomic regions that regulate gene expression—primed for stronger activation due to prior fasting experiences. These sensitized enhancers displayed increased binding of PPARα, a transcription factor critical for ketogenesis. Notably, this adaptive response was absent in hepatocyte-specific PPARα-deficient mice, highlighting PPARα’s essential role in this process.

The researchers found that the effects of ADF were evident after just one week of repeated fasting, leading to augmented production of ketone bodies during subsequent fasts. During feeding periods, gene expression and ketone levels returned to baseline, demonstrating that the sensitization effect is specific to fasting states. The health benefits of ADF, including improved lipid metabolism, appear to be linked to this enhanced ketogenic capacity rather than to changes in calorie intake or body mass, which remained largely unchanged.

Dr. Goldstein noted, “Our study highlights how the liver adapts to repeated fasting through a memory-like mechanism that prepares it for future fasting bouts. This enhancer sensitization process underscores the liver’s remarkable ability to dynamically respond to recurring nutritional states.”

The findings provide a deeper understanding of how repeated environmental signals, such as fasting, shape cellular behavior and metabolic adaptation. Beyond fasting, this research opens new avenues for exploring how transcriptional regulation mediates responses to other recurring environmental stimuli, with potential applications in dietary science and metabolic health.

The research paper titled “Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis” is now available in Nucleic Acids Research and can be accessed at https://doi.org/10.1093/nar/gkae1161 .

Researchers:

Noga Korenfeld¹, Meital Charni-Natan¹, Justine Bruse², Dana Goldberg¹, Dorin Marciano-Anaki¹, Dan Rotaro¹, Tali Gorbonos¹, Talia Radushkevitz-Frishman¹, Arnaud Polizzi², Abed Nasereddin³, Ofer Gover¹, Meirav Bar-Shimon¹, Anne Fougerat², Hervé Guillou², Ido Goldstein¹

Institutions:

1. Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. POB 12, Rehovot 7610001, Israel
2. Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
3. Genomics Applications Laboratory, Core Research Facility, Faculty of Medicine, The Hebrew University of Jerusalem-Hadassah Medical School