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Long-chain n-3 Polyunsaturated Fatty Acids Mitigate Inflammatory Adipokines Derived from Adipocyte-Macrophage Cross-talk and Ensuing Changes in M1-Macrophage Polarization Markers

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Title: Long-chain n-3 Polyunsaturated Fatty Acids Mitigate Inflammatory Adipokines Derived from Adipocyte-Macrophage Cross-talk and Ensuing Changes in M1-Macrophage Polarization Markers
Author: De Boer, Anna
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Robinson, Lindsay
Abstract: Macrophages are recruited into obese adipose tissue (AT) and interact with adipocytes to promote further macrophage recruitment and development of chronic AT inflammation, characterized by AT secreted proteins that play a role in development of pathologies, such as insulin resistance. High-fat diet-induced obesity rodent models have shown that the dietary long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), eicosapentaenoic acid (EPA) and docoshexaenoic acid (DHA), may prevent excessive AT inflammation. However, the extent to which LC n-3 PUFA modify adipocyte-macrophage cross-talk and whether this occurs through signaling mechanisms involving peroxisome proliferator-activated receptor gamma (PPARγ) or the LC n-3 PUFA upregulated anti-inflammatory adipokine, adiponectin, is not known. In this thesis, it was found that LC n-3 PUFA perturb inflammatory adipokine secretion resulting from adipocyte-macrophage cross-talk in an in vitro co-culture model designed to mimic the ratio of adipocytes:macrophages in obese AT. The addition of a potent PPARγ antagonist to co-cultures with EPA or DHA decreased adipocyte cellular adiponectin without affecting mRNA expression or protein secretion of inflammatory IL-6 and MCP-1 (CCL2). Anti-inflammatory effects of LC n-3 PUFA were also found in an in vitro co-culture model where macrophages were isolated from low or high-fat-fed mice, with or without LC n-3 PUFA, suggesting that dietary LC n-3 PUFA also blunt inflammatory adipocyte-macrophage cross-talk. Additionally, when adiponectin was neutralized in co-cultures there was a partial loss of LC n-3 PUFA-mediated suppression of M1-macrophage polarization and associated cytokine secretion, as well as NLRP3 inflammasome gene expression. Finally, such adiponectin-dependent effects were further observed in an ex vivo model, wherein adiponectin-neutralizing antibody was added to AT conditioned media from LC n-3 PUFA-fed mice prior to incubation with a murine macrophage cell line. Here, neutralizing adiponectin partly reversed LC n-3 PUFA-induced anti-inflammatory effects, including macrophage lipid uptake, mRNA expression of M1-polarization markers and NLRP3 inflammasome genes, as well as secretion of CCL2. Together, the data in this thesis suggest that LC n-3 PUFA mitigate inflammatory adipocyte-macrophage cross-talk partly through an adiponectin-mediated mechanism. Ultimately, this work supports LC n-3 PUFA as a dietary strategy to mitigate obese AT inflammation.
URI: http://hdl.handle.net/10214/9131
Date: 2015-08
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