Study Reveals How Polyphenols Lower Insulin Resistance

A new study scheduled for publication in 2024 has identified how polyphenols found in extra virgin olive oil affect the molecular and cellular mechanisms associated with cardiometabolic disease and obesity.

While more than a decade of research has demonstrated the ability of polyphenols to mitigate the negative health impacts associated with chronic inflammatory diseases, researchers still have not identified the biological mechanism through which these results are obtained.

Polyphenols are able to markedly affect gene expression profiles in diverse metabolically active tissues, and in particular, polyphenols seem to prevent some of these damages (from insulin resistance).- Enzo Nisoli, obesity researcher, University of Milan

Previous research by a team of Italian scientists identified how systemic inflammation and mitochondrial derangement and dysfunction are two of the principal mechanisms involved in the pathophysiological processes linking fat accumulation to cardiometabolic disorders, such as obesity and diabetes.

The leading hypotheses used to explain the health benefits of extra virgin olive oil on inflammatory diseases generally focus on the antioxidant properties of polyphenols to reverse the impacts of inflammation. However, researchers said this has still not been directly demonstrated.

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As a result, the Carapelli Nutritional Institute, a scientific center dedicated to the study of olive oil and funded by its parent company, Deoleo, contacted the Italian research team to study the potential molecular and cellular mechanisms involved in the beneficial effects of olive oil.

The researchers were also interested in determining the role of different components of olive oil – polyphenols, lipid derivative molecules, including squalene and tocopherols, and monounsaturated fatty acids – on the associated beneficial effects of extra virgin olive oil consumption on cardiometabolic syndromes.

Enzo Nisoli, an obesity researcher at the University of Milan and co-author of the study, said the team divided the mice into five groups and fed each group a specific diet.

The control group consumed a low-fat chow diet, where fat comprised nine percent of total calorie consumption and was comprised of soybean oil, a polyunsaturated fat.

The other four groups consumed diets containing 40 percent of calories from fat. In each diet, 14 percent of fat consumption comprised soybean oil, a source of linoleic acid, which is essential for mammal survival.

The four eating programs included a diet comprised of lard, a saturated fat; the EVO Pol+ diet, comprised of polyphenol-enriched extra virgin olive oil with squalene and tocopherol; the EVO Pol- diet, comprised of polyphenol-deprived extra virgin olive oil with squalene and tocopherol; and a hazelnut oil diet with only tocopherol.

Researchers for all groups controlled total calorie consumption and levels of exercise.

“Comparing all these diets, you can obtain information on the relevance of a single component of the extra virgin olive oil inducing eventual phenotypic and molecular differences,” Nisoli told Olive Oil Times.

The researchers performed a long experiment with the five diets controlling glucose homeostasis at various points and, at the end of the experiment, extracted white and brown adipose tissue from the liver and skeletal cells for study.

According to Nisoli, the accumulation of functional adipose tissue in diverse regions of the body “is the first stage in predisposed patients to different stages of [cardiometabolic] syndrome that can evolve into clinical cardiovascular disease or kidney disease with alterations in the heart or arteries in the brain.”

“Excess and dysfunction of adipose tissue accumulation in the body, both in animals and in humans, are able to increase inflammatory processes, oxidative stress and other things that may have the potential to disrupt the lipid metabolism in the liver,” he added, which precipitates chronic kidney disease and cardiovascular disorders.

“The major objective of our investigation was to convince the researchers that, in effect, the benefits obtained with the Mediterranean diet, through extra virgin olive oil, were obtained by modulating these alterations,” he said.

At the end of the study, Nisoli said the research team identified several significant findings, paving the way for future studies.

The researchers found that mice following the high-fat diets comprised of extra virgin olive oil could decrease their body weight compared to those following the high-fat diet containing lard.

They also observed that in all four high-fat diets, only the polyphenol-enriched diet demonstrated a statistically significant reduction in glycemia after eating.

“In addition, we performed other measurements that demonstrate that mice fed with the diet substituted with extra virgin olive oil enriched in polyphenols are less insulin resistant than high-fat lard diet and the other two extra virgin olive oil-enriched diets,” Nisoli said.

“This result is important to suggest that polyphenols are effectively involved in a normalization of glucose homeostasis and in the potential benefit in these animals,” he added.

At the end of the experiment, the researchers extracted tissues from the mice to conduct an RNA sequencing analysis that allowed them to measure the gene expression in the mice fed the polyphenol-enriched diet compared with the other diets.

These comparisons allowed the researchers to identify the genes involved in the different outcomes in the liver and the white adipose tissues and, more specifically, see how the consumption of polyphenols correlated with different gene expressions.

“When you see the same gene increased in the polyphenol-enriched high-fat diet compared to the polyphenol-deprived high-fat diet, you can see that it may be potentially involved in the pathology linked to obesity,” Nisoli said. “You may demonstrate that polyphenols are able to counteract at least partly the changes caused by obesity.”

Based on this observation, the researchers continued to analyze all the different genes and construct sequences of gene networks, known as clusters, modified by the high-fat diet and reverted by the polyphenol-enriched diet.

They found that the polyphenol-enriched diet decreased the gene expressions associated with inflammation and oxidative stress. Separately, increases in gene expressions associated with energy expenditure and mitochondrial function were observed in the mice fed the polyphenol-enriched diet.

“We concluded that if inflammation, oxidative stress and insulin resistance are the central damage caused by cardiometabolic syndrome, polyphenol-enriched extra virgin olive oil consumption prevents insulin resistance significantly,” Nisoli said.

“Polyphenols are able to markedly affect gene expression profiles in diverse metabolically active tissues, and in particular, polyphenols seem to prevent some of these damages, inflammation and oxidative stress,” he added.

While Nisoli said these results were promising in researchers’ efforts to define how extra virgin olive oil impacts the molecular mechanisms behind cardiometabolic diseases, he said there were some limitations.

Chief among these could be the different impacts of extra virgin olive oil and polyphenol consumption on gut microbiota between mice and humans, and he added that plenty of research still needs to be done before researchers can definitively say how extra virgin olive oil impacts the molecular mechanisms behind cardiometabolic diseases.

“This is the beginning of the story,” Nisoli concluded. “We are now trying to obtain more information about the genes that may be involved in the effect of the polyphenols. The research will be long.”

Study Reveals How Polyphenols Lower Insulin Resistance

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