P2-HNF4α alters linoleic acid metabolism and mitigates soybean oil-induced obesity: role for oxylipins

Oxylipins-oxidized metabolites of polyunsaturated fatty acids (PUFAs)-are associated with several pathological conditions. We previously showed that oxylipin metabolites of linoleic acid (LA) and alpha-linolenic acid positively correlate with obesity in wild-type (WT) mice fed a high fat diet (35% kcal fat) based on soybean oil (SO). Here, we compare the effect of the SO diet (10% kcal LA) to an isocaloric diet based on coconut oil (CO) that is low in LA (2% kcal) in HNF4α exon swap male mice that express only the P2 form of HNF4α (α7HMZ). α7HMZ mice gained significantly less weight on the SO diet than WT mice and exhibited neither glucose intolerance nor fatty liver as did the WT mice. Untargeted metabolomics of the liver revealed increased levels of LA and decreased levels of PUFA-derived C18 diols in α7HMZ compared to WT. Proteomics identified decreased levels of several enzymes involved in PUFA metabolism (CYP2Cs, EPHX1, FADS2, ACOX1/2) as the likely cause of decreased diols. Correlation analysis of hepatic oxylipins with body weight, coupled with a 16-weeks treatment with a soluble epoxide inhibitor (sEHI), identified the oxylipins most likely to be potential drivers of obesity as 9,10-DiHOME, 12,13-DiHOME, 9,10-DiHODE and 12,13-DiHODE. Hepatic accumulation of omega-6 and omega-3 oxylipin metabolites of the essential fatty acids, linoleic and alpha-linolenic, are necessary but not sufficient for diet-induced obesity.