title: n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-κB-dependent mechanisms.
abstract: Excessive secretion of proinflammatory adipokines has been linked to metabolic disorders. We have previously documented anti-inflammatory effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) in adipose tissue; however, the mechanisms by which these fatty acids regulate adipokine secretion remain unclear. Here, we determined differential effects of eicosapentaenoic acid (EPA, n-3 PUFA) vs. arachidonic acid (AA, n-6 PUFA) on expression and secretion of angiotensinogen (Agt), interleukin 6 (IL-6) and monocyte chemotactic protein (MCP-1) in 3T3-L1 adipocytes. While both PUFAs increased intracellular Agt protein and mRNA expression, Agt secretion into culture media was increased only by AA treatment, which in turn was prevented by co-treatment with EPA. At various AA/EPA ratios, increasing AA concentrations significantly increased secretion of the above three adipokines, whereas increasing EPA dose-dependently, while lowering AA, decreased their secretion. Moreover, IL-6 and MCP-1 were more significantly reduced by EPA treatment compared to Agt (IL-6>MCP>Agt). Next, we tested whether nuclear factor-κB (NF-κB), a major proinflammatory transcription factor, was involved in regulation of these adipokines by PUFAs. EPA significantly inhibited NF-κB activation compared to control or AA treatments. Moreover, EPA attenuated tumor necrosis factor-α-induced MCP-1 and further reduced its secretion in the presence of an NF-κB inhibitor. Taken together, we reported here novel beneficial effects of EPA in adipocytes. We demonstrated direct anti-inflammatory effects of EPA, which are at least in part due to the inhibitory effects of this n-3 PUFA on the NF-κB pathway in adipocytes. In conclusion, these studies further support beneficial effects of n-3 PUFAs in adipocyte inflammation and metabolic disorders.
authors.affiliation: Department of Animal Science, University of Tennessee (UT), Knoxville, TN, USA.
authors.forename: Nalin
authors.initials: N
authors.lastname: Siriwardhana
authors.forename: Nishan S
authors.initials: NS
authors.lastname: Kalupahana
authors.forename: Sarah
authors.initials: S
authors.lastname: Fletcher
authors.forename: Wenting
authors.initials: W
authors.lastname: Xin
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Claycombe
authors.forename: Annie
authors.initials: A
authors.lastname: Quignard-Boulange
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Saxton
authors.forename: Naima
authors.initials: N
authors.lastname: Moustaid-Moussa
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D054392:Adipokines; D000894:Anti-Inflammatory Agents, Non-Steroidal; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D000808:Angiotensinogen; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid