EPA-Derived Oxylipin Incorporation into Tissues of High-Fat Diet-Fed Mice and Its Consequences for n-6 PUFA-Derived Oxylipins.

BACKGROUND

Eicosapentaenoic acid (EPA) potentially improves metabolic and inflammatory outcomes in obesity through oxylipin biosynthesis. To study the mechanisms of EPA, researchers administer EPA-derived oxylipins to obese mice. A limitation is that tissue polyunsaturated fatty acid (PUFA)-derived nonesterified oxylipin levels upon administration of EPA-derived oxylipins is poorly studied.

OBJECTIVES

This study aimed to quantify tissue levels of 5-hydroxyeicosapentaenoic acid (5-HEPE) and 18-hydroxyeicosapentaenoic acid (18-HEPE) upon administration of these molecules to high-fat diet (HFD)-fed mice. 5-HEPE and 18-HEPE were selected as they are elevated with dietary EPA.

METHODS

C57BL/6J male mice (13 wk old) consuming an HFD were intraperitoneally administered 1 μg of 5-HEPE or 18-HEPE every 48 h over 2 wk, with the final administration 1 h before euthanasia. Four groups were analyzed: lean diet, HFD, HFD+5-HEPE, HFD+18-HEPE (5-8 mice/group). Fat/lean mass, insulin/glucose, and glucose tolerance were measured. Targeted mass spectrometry was used to quantify nonesterified oxylipins, which were analyzed via 1-way analysis of variance with a Benjamini-Hochberg correction.

RESULTS

HFD-fed mice with or without HEPEs, relative to control, were glucose intolerant but not hyperglycemic or hyperinsulinemic. Several pulmonary HEPEs were decreased by 1.5- to 3-fold (P < 0.1) with HFD compared with control. 5-HEPE and 18-HEPE administration did not elevate these oxylipins in lungs or spleen, although some pulmonary n-6 (ω-6) PUFA-derived oxylipins were decreased by ≤5-fold (P < 0.1) with 5-HEPE. Splenic PUFA-derived nonesterified oxylipins were decreased by 4- to 73-fold (P < 0.1) with 5-HEPE-treated mice. 5-HEPE and 18-HEPE administration increased plasma levels of these oxylipins by ≤3-fold (P < 0.1).

CONCLUSIONS

HFD lowered several pulmonary HEPEs, and 5-HEPE had a strong impact on unesterified oxylipin levels. 5-HEPE and 18-HEPE levels were elevated in circulation upon administration but not in lungs or spleen, suggesting rapid metabolism in these tissues or limited uptake due to the dose and timing of administration.