An extensive body of research has shown that if mothers experience stress while pregnant, the offspring can suffer ongoing psychological and development-related conditions.

Now a group of Italian researchers have shown that the biological changes induced by a ketogenic diet may help them to escape from the long-lasting effects of stress experienced in the womb.

The pregnant rats were stressed in the final week before birth. The offspring were weaned at 21 days after birth, and assigned either a control diet, or a ketogenic diet. At 42 days, the young animals were then tested for a variety of stress-induced deficits, such as poor sociability, or lack of interest in their surroundings (anhedonia). The animals which had received the ketogenic diet showed some notable differences over the control group, such as exhibiting longer grooming times, and greater sociability. The researchers found that if fed a normal diet, 50% of the rats born to stressed mothers showed stress-related problems in later life. However in those rats fed a ketogenic diet only 22% of male offspring, and 12% of female offspring, developed these problems.

The ketogenic diet has been shown to induce a variety of biological changes, such as enhancing mitochondrial efficiency and changing hormone balance.

According to lead researcher Dr. Alessia Marchesin(of the University of Milan):

"We discovered that feeding young rats a ketogenic diet -- a high-fat, very low-carbohydrate regimen -- right after weaning almost completely protected them from the lasting effects of stress they'd experienced before birth. The diet seems to have acted like a shield for their developing brains, so preventing social and motivational problems from ever taking root.

This matters because it suggests a simple way to prevent the occurrence of mood and social disorders that often originate from childhood adversity. Rather than waiting until symptoms appear and then treating them with medications -- many of which carry side effects -- we might one day take advantage of the therapeutic properties of dietary interventions early in life to prevent the manifestation of full-blown pathologic condition. What's more, we found that males and females benefited via different biological routes -- males by reducing inflammation, females by boosting antioxidant defences -- hinting that we could personalize and refine such dietary interventions.

If these findings translate to humans, we may be able to treat the long-term burden of prenatal trauma simply by adjusting what at-risk kids eat."

She added,

"There are a couple of points to note. The animals on the ketogenic diet grew more slowly than the controls, and so it may be that the reduced calory intake is associated with the later mental health benefits. And we see sex-specific differences which need to be better understood before we can apply this to humans."

Commenting, Dr. Aniko Korosi, Associate Professor at the University of Amsterdam says:

"This work nicely contributes further to the nascent field of Nutritional Psychiatry. The role of nutrition in modulating mental health is gaining attention and its potential is more and more appreciated in the field. However important questions remain in the field as to which nutrient, when and for whom are effective in modulating mental health. The presented study interestingly shows that prenatal stress-induced risk to altered behaviour can be modulated with a ketogenic diet fed after weaning. It will be intriguing to further explore what are the biological processes involved in these beneficial effects and if such effects are sex specific."

This is an independent comment, Dr. Korosi was not involved in this work.

Researchers at the University of Barcelona have now found a promising approach that could change how this condition is treated. Their study, published in Pharmacological Research, reports that two existing drugs, pemafibrate and telmisartan, significantly reduced fat buildup in animal models of metabolic liver disease. The findings also suggest that using these medications together could ease liver damage while lowering related heart and blood vessel complications. Because available treatments for this disease remain very limited, the results point to a potentially safer and more effective therapeutic option.

The research was led by Marta Alegret, a professor at the University of Barcelona's Faculty of Pharmacy and Food Sciences, and a member of the Institute of Biomedicine of the UB (IBUB) and the CIBER Area for Physiopathology of Obesity and Nutrition (CIBEROBN). The work was conducted in collaboration with scientists from the Santa Creu i Sant Pau Hospital Research Institute, the Hospital Clínic de Barcelona, the CIBER Area for Cardiovascular Diseases (CIBERCV), and Uppsala University (Sweden).

​​​​​​​Drug repurposing, a promising and cost-effective strategy

To date, most new experimental compounds developed for metabolic dysfunction-associated steatotic liver disease (MASLD) -- formerly known as fatty liver disease -- have failed during clinical trials, often because of safety concerns. This has turned attention toward drug repurposing, a strategy that explores new uses for medications already proven to be safe in humans. Such an approach is not only faster and more affordable but also particularly valuable for treating the early, often symptom-free stages of MASLD.

"We have focused on these phases with the aim of preventing the disease from progressing to more severe stages. But for a drug to be used in these early stages, it must have a good safety profile in humans," explains Marta Alegret. "That is why we have studied drugs already on the market for other pathologies, which have been shown to be very safe and could have a potential benefit in the treatment of MASLD," she adds.

In this study, the team evaluated the potential of two approved medications, given separately and together: a lipid-lowering agent (pemafibrate) and an antihypertensive drug (telmisartan). The first is marketed only in Japan, while the second is widely used for high blood pressure. Both are prescribed to reduce cardiovascular risk. "Mortality from cardiovascular causes is significant in patients with MASLD, and often these patients also have these two risk factors together," Alegret stresses.

Zebrafish larvae, an alternative model for studying the disease

To confirm the efficacy of the drugs and explore their mechanism of action, the researchers have applied them to a rat model of the disease and, subsequently, to a zebrafish larval model. "In recent years, zebrafish have emerged as an interesting alternative model that facilitates the study of the pathophysiology of MASLD and the evaluation of treatments. These are simpler and cheaper models that allow results to be obtained more quickly and which, although they are not identical to humans, have a carbohydrate/lipid metabolism and liver physiology similar to those of mammals," says the UB professor.

The results show that the combination of the two drugs reverses the fat accumulation in the liver induced by a diet high in fat and fructose. In addition, in the rat model, the combined administration of half a dose of pemafibrate and half a dose of telmisartan was found to be as effective as a full dose of either drug in reducing fat accumulation. "Combination therapy with drugs acting on different pathogenic pathways may be a better strategy than monotherapy, thanks to possible synergistic effects and reduced toxicity related to the use of lower doses of each drug," Alegret points out.

The combination of these two drugs would be beneficial not only for liver disease, but also because "it lowers blood pressure and cholesterol levels, and all this would result in a lower cardiovascular risk," she stresses.

​​​​​​​Different lipid-lowering mechanisms The study also found that each drug works by different mechanisms and describes, for the first time, the key role of the PCK1 protein in telmisartan-derived hepatic lipid lowering. "Telmisartan is a drug that has been used in other models of MASLD, but mostly in more advanced stages of the disease, and its beneficial effects have been attributed mainly to anti-inflammatory and anti-fibrotic effects. But in the early stages of the disease there is no inflammation or fibrosis yet, only lipid accumulation," explains the researcher.

Researchers have now found that the amount of PCK1 protein in the livers of MASLD animals was reduced and that treatment with telmisartan restored its levels to normal. "This increase in PCK1 diverts the flux of metabolites from lipid synthesis to glucose synthesis. This increase in glucose production could be negative if the glucose were exported and accumulated in the blood, as it could lead to diabetes, but we have noticed that this is not the case," says the UB professor.

Still far from clinical application

Despite these promising results, the researchers point out that, as this is a study using animal models, they are still far from patients. "In order to be translated into a treatment for MASLD patients, clinical studies would be needed to show that the benefits observed in animal models also occur in humans," says Alegret. ​​​​​​​ In any case, the results raise new questions, such as whether the drugs will be equally effective in more advanced stages of the disease, when fibrosis is present. The research team is therefore already working on new studies in animal models of diet-induced liver fibrosis. "In addition, we will develop a dual model involving liver fibrosis and cardiovascular disease to see if the beneficial action is observed not only in the liver, but also in the reduction of atherosclerosis," he concludes.