Endogenously Generated ω3 Fatty Acids Suppress Inflammation by Interaction with FFAR4 in Mice
Xinzhi Li1, Xinghui Che1, Ying Yu2, Colin D. Funk1，1Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada, K7L 3N6, 2Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Omega 3 polyunsaturated fatty acids (ω3 PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are recognized as agonists of free fatty acid receptor 4 (FFAR4) and can suppress inflammation. In this study, the anti-inflammatory effects of ω3 PUFAs and the potential roles of FFAR4 in vivo were investigated. The polyunsaturated fatty acid profiles of total lipids extracted from tail tissues were detected by gas chromatography. The results show lower levels of ω6 polyunsaturated acids and more abundant ω3 fatty acids in transgenic fat-1 mice (compared with their wild type littermates), where ω3 PUFAs are synthesized endogenously from ω6 PUFAs via a ω3 fatty-acid desaturase enzyme encoded by the fat-1 gene from C. elegans. It was also demonstrated that the cyclooxygenase-2 (COX-2) induction is attenuated in macrophages obtained from fat-1 mice. Transgenic fat-1 mice were then crossbred with FFAR4 knockout mice to obtain the compound Ffar4-/-/fat-1 mouse strain. mRNA expression of pro-inflammatory genes (COX-2, tumor nectosis factor-alpha, and interleukin-1 beta) are suppressed in resident macrophages of fat-1 mice, but not in those of Ffar4-/-/fat-1 mice challenged by intraperitoneal lipopolysaccharide (LPS) injection. In visceral adipose tissues, knockout of FFAR4 can partially abrogate ω3 PUFAs effects on expression of pro-inflammatory genes. Adiponectin mRNA expression in adipose tissues remains unchanged after LPS challenge and in different mouse strains. These studies provide a new mechanistic basis for the anti-inflammatory effects of PUFAs via interactions with FFAR4. Supported by a joint grant from the CIHR and NSFC (CCI 117951).