Researchers found that mice genetically engineered to express a variant of the liver protein HNF4α (called “P2-HNF4α”) are protected from obesity and fatty-liver disease even when fed a diet high in soybean oil. In contrast, normal (“wild-type”) mice on the same soybean-oil diet gained substantial weight and developed liver fat. The protective effect appears to arise from the variant HNF4α’s ability to alter how the body metabolizes the abundant omega-6 fatty acid Linoleic acid (LA), decreasing the formation of certain LA-derived metabolites (oxylipins) that are associated with fat accumulation, inflammation, and metabolic dysfunction.

This suggests that it’s not just the amount of dietary fat or LA that matters — but how individuals’ biochemistry processes it. According to the authors, genetic, enzymatic, or regulatory differences in LA metabolism may explain why some people gain weight easily on diets rich in seed oils while others do not. These findings strongly reinforce that the type of fat consumed — particularly linoleic-acid–rich seed oils — plays a decisive role in metabolic outcomes, and that how the body processes those fats can determine whether they promote obesity or protect against it.

https://www.jlr.org/article/S0022-2275(25)00195-6/fulltext