Differential Psychopathology Associations Found for Docosahexaenoic Acid versus Arachidonic Acid Oxylipins of the Cytochrome P450 Pathway in Anorexia Nervosa

Anorexia nervosa (AN) is one of the deadliest disorders in psychiatry. AN patients tend to avoid high-fat and high-calorie foods to maintain a pathologically low body weight. High-fat foods are major sources of polyunsaturated fatty acids (PUFAs), lipids that are crucial for health and brain development. PUFAs can be categorized into different omega classes (n-3, n-6) or into essential (ALA, LA) versus nonessential PUFAs (EPA, DHA, ARA). PUFAs are metabolized by Cytochrome P450 (CYP450) enzymes into bioactive oxylipins with inflammation-resolving properties termed epoxy-fatty acids (EpFAs). EpFAs are further hydrolyzed into pro-inflammatory diol-fatty acids (DiHFAs) by soluble epoxide hydrolase (sEH), the protein product of an AN risk gene, EPHX2. Using a meal challenge study protocol, EpFA and DiHFA oxylipins and sEH were analyzed in age-matched AN and healthy women to determine if sEH-associated oxylipins affect AN risk and psychopathology. At the fasting timepoint, half of the oxylipins were lower in AN compared to controls (all p<0.050). After eating, all but one EpFAs increased in AN (p=0.091 to 0.697) whereas all EpFAs decreased in controls (p=0.0008 to 0.462). By contrast, essential PUFA-derived DiHFAs significantly increased, whereas nonessential PUFA-derived DiHFAs significantly decreased in both groups. DiHFA oxylipins associated with AN psychopathology displayed a PUFA-dependent directionally opposite pattern: n-3 DHA-derived DiHFAs (DiHDPEs) were associated with lower severity in eating disorder risk, global psychological maladjustment, shape and restraint concerns, and global Eating Disorder Examination score. By contrast, n-6 ARA-derived DiHFAs (DiHETrEs) were associated with more severe emotional dysregulation, bulimia, interoceptive deficits, asceticism, and overcontrol scores. On the other hand, EpFA oxylipins were not significantly associated with AN psychopathology. This study confirms lipid metabolic dysregulation as a risk factor for AN. CYP450 oxylipins associated with AN risk and symptoms are sEH- and PUFA class-dependent. Our findings reveal that gene-diet interactions contribute to metabolic dysregulation in AN, highlighting a need for additional research to develop precision medicine for AN management.