Johanna Assies

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Johanna Assies

  1. 1. Fatty Acids in Mood Disorders Beyond ω-3 and ω-6 Johanna Assies, MD, PhDMain co-workers: Roel J.T. Mocking Anja Lok Claudi L.H. Bockting Henricus G. Ruhé Aart H. Schene François Pouwer Department of Psychiatry, University of Amsterdam Fatty Acids in Depression, Diabetes and Schizophrenia Study Group (FADDS)
  2. 2. Depressive MetS => Type 2 DM & CVD disorders FA- metabolismOxidative stress Oxidative stress 1-C-Cycle How to explain fatty acid alterations?
  3. 3. Metabolic syndrome (MetS)• Cluster of risk factors for the development of type 2 DM and CVD• Earliest and main hallmarks: insulin resistance and increased visceral fat• Hypertension, dyslipidemia, non-alcoholic steatohepatitis• Subclinical inflammation and thrombosis• Increased activity Hypothalamo-Pituitary-Adrenal (H-P-A) axis• Increased oxidative stress (↑ homocysteine, ↓ folate)
  4. 4. Fatty acids and the cell membrane• Throughout the biological world, a 30 Å hydrophobic film delimits the environments that serve as the margin between life and death for individual cells• “Membrane lipids: where they are and how they behave” G. van Meer et al. Nature 2008;9:112-124
  5. 5. Fatty acids• Essential constituents brain – Key components • Nerve cell membranes • Synapses• Regulation of cognition and emotion McNamara RK, Carlson SE 2006
  6. 6. Fatty acids• Fatty acids and oxidation products (eicosanoids and docosanoids) play an important physiological role. – Growth-development, metabolism, gene expression, signaling – Immune system, inflammation, haemostasis – ω-6 fatty acids (arachidonic acid) inflammation , haemostasis – ω-3 fatty acids (EPA) inflammation , haemostasis – – (DHA) neuroprotective
  7. 7. Methylation Methionine S-adenosyl methionine Vit B12Folate cyclus Homocysteine Methylgroups Vit B6 Cysteine PC/PE ratio Transsulfuration Gluthation Antioxidant Desaturase activity PUFA oxidation PUFA synthesis LPOs ω-3/-6 celmembrane
  8. 8. Studies so far• MDD Low intake of ω-3 PUFAs - ↓ ω-3 PUFA’s, ↑ ω-6/ω-3 PUFA’s in plasma, ery’s, AT, pm brain tissue - ↑ Lipid peroxidation products - ↑ Homocysteine, ↓ folate However, these data and supplementation studies: inconsistent results Hibbeln JR 1998, Appleton KM 2010, Suominen-Taipale AL 2010
  9. 9. FA status plasma, tissues• Diet• Endogenous metabolism Relation intake & incorporation non-linear – Genetic factors – Age, gender – (Oxidative) stress Smoking, alcohol, physical inactivity, psychological stress, dietary glucose and saturated FA. Hodson L 2008
  10. 10. Oxidative stress• To live with O2 (breathe) is most basic lifelong stress. Breathing means burning. In mitochondria food is converted to basic energy units (ATPs) with the help of molecular O2 and the formation of reactive oxygen species (ROS).• Ψυχη (soul) comes from Ψυχω (to breathe)• Oxidative metabolism tightly controlled• Oxidative stress = disbalance ROS production/ anti-oxidant defense
  11. 11. • Study population – 137 MDD-R patients – 65 age & sex matched healthy controls
  12. 12. Results Controls (n = 65) MDD-R (n = 137) p-valueWeight (kg ± SD) 73 ± 13 79 ± 16 < .05BMI ± SD 24.5 ± 3.5 26.8 ± 5.2 < .001WC (cm ± SD) 83.7 ± 12.2 89.3 ± 13.8 < .01Current depression (%) 0% (0/65) 19% (26/136) < .001 Lok A 2011
  13. 13. Results• Summarizing – In erythrocytes • SFAs and PUFAs ≥ 20 C chain length • SFAs and PUFAs < 20 C chain length • MUFAs equivocal results – In plasma ~ results, but also MUFAs < 20 C – Alterations in Desaturase and Elongase activity
  14. 14. General conclusions• Partly explained by diet but:• Effects (oxidative) stress • Genetic factors (mitochondrial dysfunction) • Presence MetS • Lifestyle: too much sugar and SFA, inadequate ω-3/ω-6 • Psychological stress, hyperactivity HPA-axis • Physical inactivity
  15. 15. Methylation Methionine - - S-adenosyl methionine Vit B12 - + - + Folate cyclus Homocysteine Methylgroups + - Vit B6 Cysteine PC/PE ratio + - Transsulfuration Gluthation Antioxidant Desaturase activity - - PUFA oxidation PUFA synthesis + - LPOs ω-3/-6 celmembrane+ Increase during oxidative stress- Decrease during oxidative stress
  16. 16. Discussion• FA alterations evolve in response to ↑ oxidative stress – (neuro)psychiatric diseases • m. Alzheimer, m. Parkinson, schizophrenia, cystic fibrosis • Family members • Normal aging – Reversible by ↓ oxidative stress
  17. 17. Hypothesis• “adaptive”/”protective” value – Lower unsaturation index (less double bonds) => more resistance against ROS) – VLCFA incorporation: ceramide, sphingomyelins, wax esters
  18. 18. Future research – Lipidomics – LPO’s – MetS – Risk factors – Anti-oxidant strategies (mitochondrial) – ↑ physical activity most effective
  19. 19. Epilogue The Brain – is wider than the Sky – For put them side by side – The one the other will contain With ease – and You – beside – Emily Dickinson
  20. 20. Scheme

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