Researchers from the University of Sydney have discovered how intermittent fasting influences key metabolic pathways in the liver. The study offers new insights into how fasting can confer certain health benefits and hypothesizes the development of specific drugs that could mimic these effects without a person needing to fast.

"We know that fasting can be an effective intervention to treat disease and improve liver health,” says Mark Larance, research lead on the University of Sydney project. “But we haven't known how fasting reprograms liver proteins, which perform a diverse array of essential metabolic functions.”

The study focused on mice subjected to an every-other-day-fasting (EODF) regime. Unlike other dietary strategies such as time-restricted feeding (where one consumes all their daily caloric intake in a six-to-eight-hour period), EODF simply involves fasting every other 24-hour period.

The primary target of the study was to investigate the metabolic effects of fasting on the liver. A cohort of mice were allowed unlimited access to food every other day for 12 days, compared to a control group with general consistent access to food.

Interestingly, while the research did reveal notable metabolic changes in the liver after 12 days, many of these improvements did not appear after one round of fasting. However, at the end of the 12-day study the researchers did identify a widespread increase in fatty acid synthesis enzymes and mitochondrial enzymes associated with increased fatty acid oxidation.

But perhaps the most novel finding in the study was the observation that fasting seemed to inhibit activity of a protein called HNF4-(alpha). The researchers suspect the down-regulation of this protein could be responsible for some of the health benefits associated with intermittent fasting.

"For the first time we showed that HNF4-(alpha) is inhibited during intermittent fasting,” says Larance. “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.”

One fascinating implication from this finding is the potential development of a drug that could specifically target this protein, recreating the effect of fasting on the liver, but without actually needing to fast.

"What's really exciting is that this new knowledge about the role of HNF4-(alpha) means it could be possible to mimic some of the effects of intermittent fasting through the development of liver-specific HNF4-(alpha) regulators," adds Larance.

It remains unclear from this study what exactly the optimum fasting regime to trigger this metabolic shift in the liver is. While the experiment does indicate recurrent fasting may be necessary, further study will hopefully uncover whether time-restricted feeding strategies can cause similar protein responses in the liver.

“It’s the fasting period itself that is causing the benefit, the molecular changes,” said Larance in an interview with The Age. “The line between alternate-day feeding or time-restricted feeding is a very grey area. If you’re fasting for 16 hours you may have the same effect as 24 hours. We chose 24 hours ... to standardize the intervention.”

The new study was published in the journal Cell Reports.

Source: University of Sydney