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  • Protease Inhibitor Cocktail (EDTA-Free, 100X in DMSO) synthe


    With ω3 able to modulate inflammation and effect obesity-related outcomes, it is of interested that two G-protein coupled receptors (GPCR), GPR120 and GPR40, were recently deorphanized and shown to recognize ω3 acids (docosahexaenoic, C22:6; eicosapentaenoic, C20:4; and α-linolenic, C18:3), as well as omega-9 (oleic acid, C18:1) [5], [6]. Following GPR120/40 activation, βarrestin2 binds to GPR120/40 and internalizes the receptor and its agonist. Concomitantly, βarrestin2 recruits the transforming growth factor beta-activated kinase1/2 binding protein (TAB1/2) from proinflammatory pathways, including Toll-like receptor (TLR) 2/4 and tumor necrosis factor alpha (TNF-α) pathways, disassembling their cascades [4], [5], [7], [8]. In addition, βarrestin2 has been shown to disrupt the structure of the inflammasome by binding to the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) protein, following ω3 fatty Protease Inhibitor Cocktail (EDTA-Free, 100X in DMSO) synthesis induced GPR120 activation, reducing the inflammation [9]. The mechanisms by which exercise has been shown to be beneficial in metabolic diseases include the decrease of TLR4 signaling improving insulin sensitivity via interleukin (IL)-6 and peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1α mediated pathways [10], [11], [12], [13]. Furthermore, exercise has been shown to increase APPL1 (adaptor protein, phosphotyrosine interaction, pleckstrin homology domain and leucine zipper containing 1), restoring insulin receptor (IR) and Akt signaling [14], as well as increasing the production of anti-inflammatory IL10. Exercise is also the accepted treatment in nonalcoholic fatty liver disease (NAFLD) [15].
    Discussion Low-grade inflammation is considered one of the most relevant mechanisms of obesity and related disturbances. It is well documented that both ω3 supplementation and physical exercise have anti-inflammatory properties in obesity as well as in improving the action of insulin [24], [25]. In this context, we focused on the association between dietary ω3 and exercise in obesity and show for the first time that chronic exercise and ω3 have a synergistic effect on the hepatic levels and anti-inflammatory signaling of the recently deorphanized GPR120, and improve metabolic and molecular parameters in obese mice. In the present study, we initially assessed whether acute physical exercise in lean mice could modulate the expression of hepatic GPR120 and GPR40 but showed no changes in either receptor at the gene or protein level (data not shown). This is in agreement with a recent study where GPR120 was shown not to be involved in the regulation of energy metabolism in lean mice during an acute physical exercise session on a treadmill [26]. Additionally, Nishinaka et al. [27] were also unable to alter GPR40 expression with acute exercise in the hippocampus of depressed mice. Next, we assessed the hepatic GPR120 and GPR40 levels in the liver of obese mice after 4 weeks of exercise training and a FS oil intervention. Of note was that the HF diet per se significantly increased the level of GPR120 compared to lean control (CT), which has previously been observed [28], [29], [30], [31], and levels were also increased both by chronic exercise and FS oil treatment. The mechanisms by which physical exercise modulates GPR120 expression have not been investigated. However, the GPR120 modulation induced by HF was recently indicated by Chen et al. [32], in which they observed that Gpr120 gene expression is under the control of the transcription factor Cebpβ. They verified an increase in Cebpβ gene expression with an HF diet, which could therefore serve as a potential candidate behind GPR120 up-regulation in our study. The observed increase in GPR120 with FS oil is also in agreement with previous studies, with ω3-supplemented diets shown to elevate GPR120 expression in animals [33] and in children diagnosed with NAFLD [34]. Here, mice subjected to the exercise training plus the FS oil treatment did not present any further increases in GPR120 compared to HF + Exe, HF + FS or HF alone.