Natasha Z Anita1, Nubaira Forkan2, Radia Kamal2, Michelle M Nguyen1, Di Yu2, Chelsi Major-Orfao3, Sophie K Wong1, Krista L Lanctôt4, Nathan Herrmann5, Paul I Oh6, Baiju R Shah7, Jeremy Gilbert8, Angela Assal8, Ilana J Halperin8, Theresa L Pedersen9, Ameer Y Taha10, Walter Swardfager11. 1. Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada. 2. Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. 3. Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada. 4. Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada; Department of Psychiatry - University of Toronto, 250 College Street 8th floor, Toronto, Ontario M5T 1R8, Canada. 5. Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Department of Psychiatry - University of Toronto, 250 College Street 8th floor, Toronto, Ontario M5T 1R8, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. 6. University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada. 7. Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. 8. Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. 9. Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA. 10. Department of Food Science and Technology, College of Agriculture and Environmental Sciences, University of California, Davis, CA, USA; NIH-West Coast Metabolomics Center, Genome Center, University of California - Davis, Davis, CA, USA. 11. Department of Pharmacology & Toxicology - University of Toronto, Medical Sciences Building, 1 King's College Circle Room 4207, Toronto, Ontario M5S 1A8, Canada; Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; University Health Network Toronto Rehabilitation Institute - Rumsey Centre Cardiac Rehabilitation, 347 Rumsey Rd, East York, Ontario M4G 2V6, Canada. Electronic address: w.swardfager@utoronto.ca.
Abstract
BACKGROUND: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. METHODS: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. RESULTS: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). CONCLUSIONS: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.
BACKGROUND: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. METHODS: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. RESULTS: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). CONCLUSIONS: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.
Authors: Christian B Bergmann; Cindy B McReynolds; Debin Wan; Nalin Singh; Holly Goetzman; Charles C Caldwell; Dorothy M Supp; Bruce D Hammock Journal: Proc Natl Acad Sci U S A Date: 2022-03-21 Impact factor: 12.779