Soybean oil (SO), one of the most widely used cooking oils in the US and a staple in many processed foods, is regarded as benign or even beneficial when compared with saturated fat.

But new research suggests SO may contribute to weight gain and postulates a potential mechanism behind this effect. Although the study was conducted in mice, the researchers said it could have implications for humans.

“Soybean oil isn’t toxic per se. But the quantities in which we consume it are triggering pathways our bodies didn’t evolve to handle,” senior author Frances Sladek, PhD, professor of cell biology and toxicologist, Department of Cell, Molecular, and Systems Biology, University of California Riverside, told Medscape Medical News.

The study was published online in the Journal of Lipid Research.

‘Master Regulator’

Composed of primarily polyunsaturated fatty acids (PUFAs), SO is rich in linoleic acid (LA), an essential omega-6 fatty acid. The consumption of SO has “remarkably increased” in the past century, according to the authors.

“We were concerned about the ever-increasing rates of obesity in the US. We learned from a seminal study that SO is the single component that has changed the most in the American diet over the past 100 years — more than chicken and more than fructose,” said Sladek and lead author Sonia Deol, PhD, assistant research professor, University of California Riverside, in an e-mail to Medscape Medical News.

Their previous research suggested that oxylipins — downstream bioactive metabolites of PUFAs — are associated with several metabolic and inflammatory conditions, notably obesity. In particular, they showed that oxylipin metabolites of LA and alpha-LA(ALA) were associated with obesity in male mice who were fed a high-fat diet rich in SO.

LA is a ligand for hepatocyte nuclear factor alpha (HNF4-alpha), a protein manufactured in the liver that regulates the expression of numerous genes that play a role in fat metabolism, Deol and Sladek explained. “HNF4-alpha is considered to be the ‘master regulator’ of liver-specific gene expression,” they said.

HNF4-alpha exists in two major isoforms — P1- and P2-driven. Although P1 tends to predominate, P2 can be induced under certain conditions (eg, metabolic stress, fasting, and liver disease).

“We thought this variation in HNF4-alpha isoforms, together with other differences like age, sex, medications, and genetics, may shed light on the reason some people gain weight from SO, while others don’t.”

Results of previous experiments found that mice whose HNF4-alpha gene was altered to produce only the P2 isoform (alpha-7HMZ mice) had decreased expression in the liver of some of the enzymes that metabolize LA.

“So we thought we might see a different response to SO in these mice,” the researchers said. “We wanted to understand why one of the most widely consumed edible oils in the world leads to more obesity than other types of fats.”

More Isn’t Necessarily Better

In the current study, the researchers compared the effect of the LA-rich SO diet to an isocaloric diet based on coconut oil, which is low in LA. These two high-fat diets were fed to alpha-7HMZ mice and to ordinary wild-type (WT) mice. Standard lab chow was fed to a third group of mice, who were used as a low-fat control group.

Following the feeding period, the researchers harvested liver samples and performed targeted lipidomic and proteomic analyses, quantifying LA, ALA, their downstream metabolites, and the enzymes that metabolize them.

The alpha-7HMZ mice gained significantly less weight on the SO diet than the WT mice and exhibited insulin resistance. Notably, oxylipin levels in the liver rather than in the blood correlated with body weight, “suggesting that blood tests would not accurately capture early metabolic changes related to the SO diet,” Deol and Sladek said.

The livers of the alpha-7HMZ mice exhibited significantly fewer oxylipins, relative to WT mice. Enzymes involved in the metabolism of LA and ALA showed reduced expression or activity in the alpha-7HMZ mice, who also showed superior mitochondrial function. “This suggests a potential role for mitochondria in the resistance to diet-induced obesity and might explain why these mice gained less weight,” Deol and Sladek said.

“Our research showed that diets high in SO can cause obesity and can also increase intestinal inflammation, make the gut microbiome less beneficial, and drastically alter the gene expression in the liver, intestines, and hypothalamus,” they said.

“This suggests that SO, or any other dietary component that is ubiquitous in our diet, should not be seen as a ‘free ride,’” they added. “You cannot assume that just because a small amount of something is good for you, a lot more of it will be better.”

Further research should determine whether these findings can be generalized to other PUFAs and to human beings.

Intriguing, but Don’t Avoid SO

Commenting for Medscape Medical News, Marion Nestle, PhD, MPH, professor of nutrition, food sciences, and public health, emerita, New York University, New York City, wondered “what this complicated mouse study has to do with human nutrition.”

Since fat has more than twice the calories of protein and carbohydrates, “not eating too much of any kind [of fat] might help with weight maintenance,” said Nestle, a visiting professor of nutritional sciences at Cornell University, Ithaca, New York.

Also commenting for Medscape Medical News, Scott Isaacs, MD, president of the American Association of Clinical Endocrinology, called the findings “scientifically intriguing but not a reason for people to avoid SO.”

The study “underscores that fat quality matters and suggests there may be nuanced differences among specific monounsaturated fatty acids and PUFAs; but it remains hypothesis-generating,” said Isaacs, an adjunct assistant professor of medicine, Emory University, Atlanta. “More human research is needed before changing dietary advice for patients.”

This study was supported by grants from the National Institute of Environmental Health Sciences and the National Institutes of Health. Deol, Sladek, the other authors, and Isaacs reported no relevant financial relationships. Nestle reported receiving royalties and honoraria for books and lectures about food politics.

Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).