The mouse model supports the importance of fatty acid balance in chronic diseases

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The mouse model supports the importance of fatty acid balance in chronic diseases

Using new transgenic mouse models they have developed, researchers at Massachusetts General Hospital (MGH) have provided new evidence that it is the ratio of omega-6 and omega-3 fatty acids, rather than their total amount, that influences the risk of developing a chronic disease. This work has important implications for wellness and nutrition guidelines. Their article has just been published in Nature's Communications Biology.

"It is important to understand the differential effects of these two categories of polyunsaturated fatty acids on the development of chronic diseases, but it is a challenge because of confounding dietary factors. We have developed a unique approach to address this," says the study's lead author, Jing X. Kang, MD, PhD, Director of the Laboratory for Lipid Medicine and Technology at MGH and Associate Professor of Medicine at Harvard Medical School. The team led by Kang has created several new mouse models to study the health effects of omega-6 and omega-3 fatty acids.

The role of polyunsaturated fatty acids (PUFAs) in human health has long been debated, but is of great interest. This is one of many factors that can influence chronic diseases, such as obesity, type 2 diabetes, cardiovascular disease and cancer, but studies have shown inconsistent results as to their exact impact on risk. The new article by the MGH researchers provides important new evidence in this area by using mouse models that help to eliminate some of the countless confounding dietary factors that affect studies in this field. The transgenic mice used are identical, except for the levels of n-6 and n-3 that they naturally produce, regardless of their diet.

The researchers used four mouse strains for their study, a wild-type or "normal" mouse, followed by three related mouse strains designed to produce different levels of n-6 and n-3 PUFAs, regardless of their diet. These mice can synthesize sufficient levels of specific PUFAs to take into account dietary factors that would normally disrupt PUFA levels.

The MGH team investigated whether the four types of mice had different rates of metabolic disorders, including metabolic endotoxemia, systemic inflammation, obesity, fatty liver, glucose intolerance and cancer. Mice that overproduced n-6 PUFAs had a higher risk of metabolic disease and cancer, while mice capable of converting n-6 to n-3, thus reducing the ratio, had a healthier phenotype. Researchers were also able to discover details on the molecular interactions between these fatty acids and biological networks. For example, changes in the n-6 to n-3 ratio of the PUFA resulted in changes in intestinal microbiome, fecal and serum metabolites.

"The beauty of these mouse models is that they reduce confounding effects," explains the study's lead author, Kanakaraju Kaliannan, MD, MGH investigator of the study and medical instructor at Harvard Medical School. "We can use them to study many other things, including the specific impact of PUFA levels on disease risk."

"There are now many data sources that support the idea that the imbalance between omega-3 and omega-6 is a critical factor contributing to the development of chronic diseases," added Ms. Kang. "Balancing the level of PUFAs can be a safe and effective solution to some modern health problems." His team is currently working on translational research to explore the clinical utility of the balancing intervention and the feasibility of using the omega-6/omega-3 ratio in tissues as a new health biomarker.