Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover.
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.
McNamara
Robert K
RK
Department of Psychiatry, University of Cincinnati College of Medicine, 260 Stetson Street, Suite 3306, Cincinnati, OH 45219-0516, USA. robert.mcnamara@uc.edu
Jandacek
Ronald
R
Rider
Therese
T
Tso
Patrick
P
Cole-Strauss
Allyson
A
Lipton
Jack W
JW
D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000172:deficiency; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D012701:Serotonin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017962:alpha-Linolenic Acid / Q000378:metabolism
D016207:Cytokines; D015525:Fatty Acids, Omega-3; D018836:Inflammation Mediators; D015850:Interleukin-6; D008055:Lipids; D014409:Tumor Necrosis Factor-alpha; D017962:alpha-Linolenic Acid; D012701:Serotonin; D002097:C-Reactive Protein
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