Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover

Prostaglandins Leukot Essent Fatty Acids. 2010 Oct-Dec;83(4-6):185-91. doi: 10.1016/j.plefa.2010.08.004.


Omega-3 (n-3) fatty acid deficiency, elevated inflammatory signaling, and central serotonin (5-HT) turnover have separately been implicated in the pathophysiology of major depressive disorder (MDD). In the present study we investigated the interrelationship between n-3 fatty acid status, pro-inflammatory signaling activity, and central 5-HT turnover in vivo. Rats were fed diets with or without the n-3 fatty acid precursor α-linolenic acid (ALA) during perinatal development (E0-P100), and a subset of rats fed the ALA- diet were switched to the ALA+ diet post-weaning (P21-P100, repletion). In adulthood (P100), plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and C-reactive protein (CRP) levels were measured. Additionally, indices of liver n-6 fatty acid biosynthesis, erythrocyte fatty acid composition, and regional brain monoamine turnover were determined. Indices of liver delta-6 desaturase activity were up-regulated in n-3-deficient rats, and were associated with greater erythrocyte membrane arachidonic acid (AA, 20:4 n-6) composition. Plasma IL-6 (p=0.001), TNFα (p=0.02), and CRP (p=0.001) concentrations were significantly greater in n-3-deficient rats relative to controls. The 5-HIAA/5-HT ratio was significantly greater in frontal cortex, hypothalamus, and ventral striatum of n-3-deficient rats relative to controls. Changes in membrane n-3 and n-6 fatty acid composition, elevations in plasma IL-6 and TNFα, and increased central 5-HT turnover were all prevented by normalization of n-3 fatty acid status. Erythrocyte docosahexaenoic acid (DHA, 22:6 n-3) was inversely correlated, and AA and the AA/DHA and AA/eicosapentaenoic acid ratios were positively correlated, with plasma IL-6, TNFα, and CRP levels. Plasma IL-6 levels were positively correlated with 5-HIAA/5-HT ratios in all brain regions. These preclinical data provide evidence for a functional link between n-3 fatty acid deficiency, elevated peripheral inflammatory signaling, and increased central 5-HT turnover.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • C-Reactive Protein / metabolism
  • Cytokines / biosynthesis*
  • Fatty Acids, Omega-3 / metabolism*
  • Female
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / metabolism
  • Lipids / deficiency
  • Male
  • Rats
  • Rats, Long-Evans
  • Serotonin / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • alpha-Linolenic Acid / metabolism


  • Cytokines
  • Fatty Acids, Omega-3
  • Inflammation Mediators
  • Interleukin-6
  • Lipids
  • Tumor Necrosis Factor-alpha
  • alpha-Linolenic Acid
  • Serotonin
  • C-Reactive Protein