Why soybean oil may fuel weight gain

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Dec 4 2025

Study: P2-HNF4α Alters Linoleic Acid Metabolism and Mitigates Soybean Oil-Induced Obesity: Role for Oxylipins. Image Credit: crystal light / Shutterstock.com

A recent study published in the Journal of Lipid Research examines how a soybean-oil–based high-fat diet alters liver fat metabolism and drives obesity in mice, with potential implications for human metabolic health.

LA, PUFAs, and metabolic risk

The global consumption of polyunsaturated fats (PUFAs) has increased significantly over the past several decades. Soybean oil (SO) is a rich source of PUFAs, which are high in linoleic acid (LA), an essential omega-6 (ω-6) fatty acid.

Relatively small amounts of LA are essential for human health. However, increased dietary LA intake can increase the risk of various metabolic and inflammatory diseases, including obesity. For example, a positive correlation between higher hepatic oxylipins derived from LA and alpha-linolenic acid (ALA) with SO-induced obesity in male mice has been observed.

HNF4α as a regulator of liver lipid metabolism

LA is a natural ligand for hepatocyte nuclear factor 4 α (HNF4α), a nuclear receptor involved in regulating liver-specific gene expression. HNF4α is a highly conserved transcription factor associated with inflammatory bowel disease (IBD), cancer, hemophilia, and diabetes.

Experimental findings suggest that HNF4α may be involved in diet-induced obesity and metabolic syndrome. A high-SO diet led to obesity in wild-type (WT) male mice that express primarily HNF4α1/2 in the liver. Researchers have identified a significant decrease in some cytochrome P450 (Cyp) genes that metabolize LA to oxylipins in the livers of exon-swap mice. These mice express only the P2 Isoform of HNF4α, referred to as α7HMZ.

Soybean oil vs. coconut oil diets

The researchers of the current study investigated the effects of a soybean oil (SO) diet containing 10 % kcal linoleic acid (LA) compared to an isocaloric diet based on coconut oil (CO) containing 2% kcal LA in male mice that express only the P2 form of HNF4α (α7HMZ). Standard lab chow, which is also referred to as vivarium chow (Viv), served as a low-fat control diet.

Wild-type (WT) male mice that primarily express P1-HNF4α in the liver, as well as α7HMZ mice that only express the P2-HNF4α isoform, were randomly assigned to consume SO+CO, CO, or a low-fat diet.

Food intake was recorded twice a week, whereas body weight was measured once a week for up to 35 weeks. After the experimental period, mice were euthanized, and their tissues were collected according to standard procedures.

P2- HNF4α protects mice from soybean oil-induced obesity

The α7HMZ mice consuming low-fat and CO diets did not exhibit a significant difference in their body weight measurements as compared to WT mice, indicating no inherent growth defect and normal fat absorption. However, α7HMZ mice consuming the SO+CO diet gained significantly less weight than WT mice consuming the SO+CO diet. Weight gain for α7HMZ mice was similar between CO and SO+CO groups, whereas WT mice consuming SO+CO gained 411 % of their starting weight, compared to 370 % in the CO group.

White adipose tissue (WAT) accumulation, especially in mesenteric and subcutaneous regions, was significantly lower in α7HMZ mice consuming SO+CO as compared to WT. WAT weights were similar between genotypes in the low-fat diet groups; however, α7HMZ mice consuming the CO diet exhibited slightly more perirenal fat than WT.

Moreover, α7HMZ mice fed the SO+CO diet had a lower liver-to-body weight ratio than WT and chow-fed α7HMZ mice, along with smaller liver fat droplets. Both α7HMZ and WT mice on the CO diet had minimal liver fat accumulation, which is consistent with prior observations.

SO+CO increased glucose intolerance in WT mice as compared to Viv, while both high-fat diets increased glucose intolerance in α7HMZ mice, though α7HMZ on SO+CO were less affected than WT.

Insulin resistance increased in α7HMZ mice on CO but not SO+CO. In WT mice, both CO and SO+CO increased insulin resistance as compared to the control diet, whereas only SO+CO previously led to this effect.

Liver metabolomic analysis revealed that 45 primary metabolites differed between WT and α7HMZ mice on the SO+CO diet. A total of 33 metabolites were unique to the SO+CO diet.

Four metabolites, including 3-hydroxybutyric acid, glycerol-alpha-phosphate, lyxitol, and N-methylalanine, were upregulated in α7HMZ mice on CO and SO+CO diets, suggesting a combined effect of HNF4α isoforms and fat intake. Three trichloroacetic acid (TCA) cycle intermediates were elevated in α7HMZ SO+CO livers but decreased in WT, which reflects the role of HNF4α in mitochondrial function and energy metabolism.

Metabolomic analysis revealed that the SO+CO diet had a significant impact on LA metabolism. LA and its metabolite, arachidonic acid (ARA), accumulated in α7HMZ livers following SO+CO intake, but not in WT mice, where LA levels decreased.

The accumulation of fatty acids in WT mice on the CO diet was myristic, palmitoleic, and oleic acids, which were most elevated in WT mice on the CO diet, thus reflecting the fatty acid composition of coconut oil.

Conversion to oleic acid was reduced by soybean oil in the SO+CO diet. These fatty acids did not accumulate in α7HMZ mice; however, a greater proportion of ketone bodies derived from these compounds was observed in α7HMZ mice on the CO diet.

Lower levels of LA/ALA diols in the liver were associated with resistance to soybean oil-induced obesity, supporting previous findings that higher hepatic oxylipins in WT mice are associated with obesity.

HNF4α exon-swap mice, which are resistant to SO-induced obesity, exhibited elevated liver LA levels. This indicates that LA itself is not responsible for obesity; rather, obesity is more closely related to the ratio of LA/ALA and their corresponding LA/ALA diol metabolites.

Additionally, α7HMZ mice consuming the soybean diet showed high levels of glycerol-3-phosphate and β-hydroxybutyric acid, thus indicating enhanced mitochondrial activity in P2-HNF4α. In contrast, WT mice on the soybean oil diet exhibited lower levels of TCA cycle intermediates, suggesting impaired mitochondrial function and lower energy expenditure.

Conclusions

Future studies are needed to clarify how the identified oxylipins contribute to obesity, including their effects on specific genes, proteins, and cellular systems. A comprehensive metabolite analysis is also warranted to explain the interactions between oxylipins and inflammation, as well as their effects on mitochondrial function.