Fasting has long been a cornerstone of spiritual and religious practices worldwide, from Ramadan in Islam and Yom Kippur in Judaism to Lent in Christianity and various fasting traditions in Hinduism and Buddhism. These traditions often involve repeated fasting periods, raising fascinating questions about how our bodies adapt to such patterns. In recent years, fasting has also gained popularity as a health trend, with methods like intermittent fasting and time-restricted eating touted for their potential benefits, including improved metabolism and longevity. A new study from the Hebrew University of Jerusalem sheds light on how the liver adapts to repeated fasting, revealing a memory-like mechanism that enhances metabolic responses during future fasts.

 

Published in Nucleic Acids Research, the study was led by Dr. Ido Goldstein from the Hebrew University's Institute of Biochemistry, Food Science, and Nutrition. The team discovered how alternate-day fasting (ADF) triggers a cellular memory mechanism in the liver. This process primes the liver for future fasting events, enhancing its ability to produce ketone bodies, a key energy source during fasting.

 

How the Liver Adapts

Fasting induces metabolic changes that enable mammals to produce glucose and ketone bodies for energy during food scarcity. Dr. Goldstein’s team explored how recurring fasting events influence these processes, focusing on transcriptional changes (how genes are turned on and off) in the liver.

 

Their findings showed that mice undergoing ADF adapted significantly better to subsequent fasting compared to those fasting for the first time. This adaptation, termed “sensitization,” involved key genes linked to ketogenesis (the production of ketone bodies) becoming more strongly activated due to prior fasting experiences.

 

The Role of PPARα

The study identified changes in the liver’s chromatin—DNA structures that regulate gene activity—that enabled this enhanced response. Specifically, genomic regions called enhancers became "primed" for activation, increasing their sensitivity to the transtranscription factor PPARα, which plays a critical role in ketogenesis.

 

The researchers confirmed PPARα's central role by studying mice lacking this factor in liver cells. These mice did not exhibit the same adaptive response, underscoring the transcription factor's importance importance in fasting-induced liver memory.

 

Key Findings

• Rapid Sensitization: The liver began adapting after just one week of alternate-day fasting.
• Targeted Response: The enhanced gene activity was specific to fasting periods, with normal gene expression resuming during feeding.
• Health benefits: Improved lipid metabolism appeared to be linked to the enhanced ketogenic capacity, independent of calorie intake or body weight changes.

 

Implications for Health

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

 

The findings offer valuable insights into the metabolic benefits of fasting, providing a deeper understanding of how the body adjusts to environmental signals over time. Beyond fasting, this research opens doors for exploring similar mechanisms in response to other recurring environmental stimuli, with potential applications in dietary science and metabolic health.

 

Learn More

The full study, titled “Repeated fasting events sensitize enhancers, transcription factor activity and gene expression to support augmented ketogenesis,” is available in Nucleic Acids Research. Access it here: https://doi.org/10.1093/nar/gkae1161.

 

Research Team and Affiliations:

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

 

The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The University’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 81st according to the Shanghai Ranking. To learn more about the University’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en