A University of Sydney-led research team has employed a multi-omics approach using state-of-the-art analytical tools to understand how intermittent fasting impacts on the liver to help prevent disease. The results revealed that every-other-day-fasting (EODF) in mice impacted fatty acid metabolism, and was associated with inhibition of the transcription factor HNF4a, which regulates a large number of genes, but which hadn’t previously been linked with intermittent fasting. The team says the findings could help point to new interventions that lower disease risk and discover the optimum intervals for fasting.

“We know that fasting can be an effective intervention to treat disease and improve liver health,” said Mark Larance, PhD, a Cancer Institute of NSW future research fellow in the Charles Perkins Centre and School of Life and Environmental Sciences at the University of Sydney. “But we haven’t known how fasting reprograms liver proteins, which perform a diverse array of essential metabolic functions. For the first time, we showed that HNF4a is inhibited during intermittent fasting. This has downstream consequences, such as lowering the abundance of blood proteins in inflammation or affecting bile synthesis. This helps explain some of the previously known facts about intermittent fasting.”

Larance and colleagues reported on their experiments and findings in Cell Reports, in a paper titled, “Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4a.” The study was carried out in collaboration with scientists at the Heart Research Institute and with John O’Sullivan, PhD, at Royal Prince Alfred Hospital. O’Sullivan is an adjunct professor in the faculty of medicine & health and a senior lecturer at the Sydney Medical School.

Nutrient deprivation diets have become popular in the treatment of metabolic disease, the authors wrote, but scientists have limited data on the mechanisms by which they affect metabolism. There are three basic strategies they explained: chronic caloric restriction (CCR); time-restricted feeding (TRF); and intermittent fasting (IF). The simplest IF regime is EODF, when no food is consumed on alternate days. Studies in mice have shown that this approach is associated with increased lifespan, improved insulin sensitivity, reduced fasting blood glucose levels, and decreased total blood cholesterol levels, but without weight loss. “Together, this evidence implies that the metabolic benefits of IF are unique to the repeated bouts of fasting and can be dissociated from the metabolic benefits of long-term weight loss,” the scientists commented.

Mark Larance, PhD, from the Charles Perkins Centre and School of Life and Environmental Sciences at the University of Sydney. [Stefanie Zingsheim/University of Sydney]

Despite these observations, and unlike acute fasting, “the molecular regulation of the beneficial EODF phenotype is not well understood,” the team acknowledged. For their studies, the team employed a multi-omics approach to identify how EODF affected proteins in the liver. “This analysis focused on the liver, which is a key fasting responsive organ and likely mediates many of the beneficial effects of IF,” they stated. The multi-omics approach considers multiple data sets, which allows scientists to evaluate a complete array of proteins and genes, and enables the integration of large amounts of information to discover new associations within biological systems. The multi-omics data was obtained at Sydney Mass Spectrometry, part of the University of Sydney’s Core Research Facilities. As O’Sullivan noted, “These multi-omics approaches give us unprecedented insight into biological systems. We are able to build very sophisticated models by bringing together all the moving parts.”

The results of the investigators’ studies in mice found that EODF impacted on proteins in the liver, and on fatty acid metabolism, a finding that could be applied to improvements in glucose tolerance and the regulation of diabetes, the authors suggested. In particular, EODF was shown to inhibit the transcription factor HNF4a, which was linked with downregulation of HNF4a targets. “Suppressed HNF4a targets include bile synthetic enzymes and secreted proteins, such as a1-antitrypsin or inflammatory factors, which reflect EODF phenotypes,” they stated. “We subsequently demonstrated that HNF4a-chromatin binding was inhibited, and this was upstream of the large decrease in liver a1-antitrypsin protein abundance observed during EODF.”

Proteomic analysis of the EODF animals’ plasma also confirmed that the changes in the liver translated to a significant decrease in a1-antitrypsin levels in plasma, together with similar changes in other secreted HNF4a target proteins, such as inflammation-associated proteins. The team concluded, “These data provide the first system-wide view of changes generated by IF and highlight key pathways and transcription factors regulated during the response that may facilitate the beneficial effects of this dietary regime.” Larance further commented, “What’s really exciting is that this new knowledge about the role of HNF4a means it could be possible to mimic some of the effects of intermittent fasting through the development of liver-specific HNF4a regulators … Last year we published research into the impact of every-other-day-fasting on humans. Using these mouse data, we can now build up improved models of fasting for better human health.”

The researchers have generated an interactive visualization of their data, which they are making freely available online at https://www.larancelab.com/eodf.

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