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. 2018 Sep 21;10(10):1351.
doi: 10.3390/nu10101351.

Endogenous Omega (n)-3 Fatty Acids in Fat-1 Mice Attenuated Depression-Like Behavior, Imbalance between Microglial M1 and M2 Phenotypes, and Dysfunction of Neurotrophins Induced by Lipopolysaccharide Administration

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Endogenous Omega (n)-3 Fatty Acids in Fat-1 Mice Attenuated Depression-Like Behavior, Imbalance between Microglial M1 and M2 Phenotypes, and Dysfunction of Neurotrophins Induced by Lipopolysaccharide Administration

Minqing Gu et al. Nutrients. .

Abstract

n-3 polyunsaturated fatty acids (PUFAs) have been reported to improve depression. However, PUFA purities, caloric content, and ratios in different diets may affect the results. By using Fat-1 mice which convert n-6 to n-3 PUFAs in the brain, this study further evaluated anti-depressant mechanisms of n-3 PUFAs in a lipopolysaccharide (LPS)-induced model. Adult male Fat-1 and wild-type (WT) mice were fed soybean oil diet for 8 weeks. Depression-like behaviors were measured 24 h after saline or LPS central administration. In WT littermates, LPS reduced sucrose intake, but increased immobility in forced-swimming and tail suspension tests. Microglial M1 phenotype CD11b expression and concentrations of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17 were elevated, while M2 phenotype-related IL-4, IL-10, and transforming growth factor (TGF)-β1 were decreased. LPS also reduced the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (Trk B), while increasing glial fibrillary acidic protein expression and pro-BDNF, p75, NO, and iNOS levels. In Fat-1 mice, LPS-induced behavioral changes were attenuated, which were associated with decreased pro-inflammatory cytokines and reversed changes in p75, NO, iNOS, and BDNF. Gas chromatography assay confirmed increased n-3 PUFA levels and n-3/n-6 ratios in the brains of Fat-1 mice. In conclusion, endogenous n-3 PUFAs may improve LPS-induced depression-like behavior through balancing M1 and M2-phenotypes and normalizing BDNF function.

Keywords: BDNF; Fat-1 transgenic mice; depression; microglial M1 and M2 phenotypes; n-3 fatty acids; neurotrophins.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Timeline of the experimental procedures. SPT: sucrose preference test; TST: tail suspension test; FST: forced swimming test; LPS: lipopolysaccharide.
Figure 2.
Figure 2.
LPS decreased sucrose preference in wild-type mice, which was not reversed in Fat-1 mice. ** p < 0.01 vs. WT/saline. LPS: lipopolysaccharides; WT: Wild-type.
Figure 3.
Figure 3.
LPS increased immobility time in tail suspension test (TST), which was significantly reversed in Fat-1 mice. *** p < 0.001 vs. WT/saline; ### p < 0.001 vs. WT/LPS. LPS: lipopolysaccharides; WT: Wild-type.
Figure 4.
Figure 4.
LPS increased immobility time in forced-swimming test (FST), which was attenuated in Fat-1 mice. *** p < 0.001 vs. WT/saline; ## p < 0.01 vs. WT/LPS. LPS: lipopolysaccharides; WT: Wild-type.
Figure 5.
Figure 5.
LPS up-regulated interleukin (IL)-1β, IL-17, and tumor necrosis factor (TNF)-α concentration significantly in WT littermates. These changes were markedly attenuated in Fat-1 mice. (A) IL-1β; (B) IL-17; (C) TNF-α. ** p < 0.01, *** p < 0.001vs. WT/saline; # p < 0.05, ### p < 0.001 vs. WT/LPS. LPS: lipopolysaccharides; WT: Wild-type.
Figure 6.
Figure 6.
LPS decreased the concentration of IL-10, IL-4 and transforming growth factor (TGF)-β1, but increased IL-13. These abnormalities were attenuated significantly in Fat-1 mice for IL-10, IL-4, TGF-β1, and IL-13. (A) IL-10; (B) TGF-β1; (C) IL-4; (D) IL-13. * p < 0.05, *** p < 0.001 vs. WT/saline; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. WT/LPS. LPS: lipopolysaccharides; WT: Wild-type.
Figure 7.
Figure 7.
LPS increased iNOS and NO concentration. These increases were attenuated in Fat-1 mice signally. (A) iNOS; (B) NO. *** p < 0.001 vs. WT/saline; ## p < 0.01, ### p < 0.001 vs. WT/LPS. LPS: lipopolysaccharides; WT: Wild-type.
Figure 8.
Figure 8.
LPS up-regulated the mRNA expression of CD11b, GFAP, and p75, and down-regulated mRNA expression of BDNF in the LPS model. mRNA expression of CD11b and p75 were decreased in Fat-1 mice when compared with WT/LPS-challenged group. (A) CD11b; (B) GFAP; (C) BDNF; (D) p75; (E) Trk B. * p < 0.05, ** p < 0.01 vs. WT/saline; # p < 0.05, ## p < 0.01 vs. WT/LPS. GFAP: glial fibrillary acidic protein; BDNF: brain-derived neurotrophic factor; LPS: lipopolysaccharides; WT: Wild-type.
Figure 9.
Figure 9.
LPS significantly up-regulated the protein expression of CD11b, GFAP, p75, and pro-BDNF, but down-regulated protein expression of BDNF and Trk B in the animal model. The protein expression of GFAP was increased in Fat-1 mice when compared with wild-type mice. The rise in the protein expression of CD11b and p75 was prevented, and there was an up-regulation of BDNF level at the same time in Fat-1 mice. (A) CD11b; (B) GFAP; (C) pro-BDNF; (D) BDNF; (E) Trk B; (F) p75. * p < 0.05, ** p < 0.01 vs. WT/saline; # p < 0.05 vs. WT/LPS; && p < 0.01 vs. Fat-1/saline. LPS: lipopolysaccharides; WT: Wild-type. S: saline.

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