Modulation of gene expression of GPR fatty acids sensors/receptors by dietary fatty acids influences inflammatory response in adipocytes

The fate of dietary fatty acids is finely regulated by specific cellular receptors capable of sensing the quantity and the quality of fatty acids reaching different organs via lipoproteins or as free fatty acids (FFAs). These receptors named GPR fatty acids receptors/sensors seem to play a fundamental role in governing the fate of dietary fatty acids in adipocytes. Based on these features, in this work we evaluated the effect of free fatty acids on inflammatory markers and the involvement of GPR120 and GPR84 in modulating the inflammatory response in obesity as assessed in human adipocytes. Cells were differentiated and incubated at 12 days post-induction of differentiation with inflammatory cytokines, hormones or fatty acids for 4 and 24 h. Both TNFα (tumor necrosis factor-α) and IL-1β induced a reduction in GPR120 expression at 4h and 24 h. In marked contrast, GPR84 mRNA level was dramatically increased by treatment with the pro-inflammatory cytokines. The PPARγ agonist rosiglitazone had no effect on GPR84 expression, but there was a stimulation of GPR120 expression which was most marked at 24 h. Dexamethasone and insulin had little or no effect on GPR120 and GPR84 expression. Docosahexaenoic acid (DHA) was able to increase GPR120 gene expression only after 24h of incubation while arachidonic acid (ARA) strongly decreased GPR120 gene expression at the same time point; both had no effect on GPR84 expression. The GPR FFA receptors are sensitive to circulating levels of FFAs. In order to evaluate whether concentration of free DHA present in human plasma changes based on its dietary intake, we carried out a pilot study. Normalweight, overweight and obese subjects were treated with an intake of 2 g/d of EPA/DHA supplements in two different formulations: fish oil (FO) and Krill oil (KO). Control group was treated with olive oil (OO). Plasma free fatty acids, particularly those relevant for the effects on GPRs, namely EPA (eicosapentenoic acid), DHA, POA (palmitoleic acid) and ARA and also the plasmatic level of TNFα were taken into consideration. In overweight and obese subjects FO was more efficient in increasing plasma free DHA and POA, while in the case of KO it was EPA even though not significantly. In addition, we found that free ARA decreased with FO treatment leading to an increase of DHA/ARA ratio. This increase mirrored the decrease of TNFα. Interestingly the increase of DHA and POA was associated to a decrease of circulating TNFα. The changes were only evident in the obese subjects probably because they had higher levels of circulating FFAs, and higher concentration of TNFα. Therefore, our data suggest that KO, as opposite to FO, being mostly incorporated into PLs, decreases circulating FFAs and thereby DHA and POA, with a possible less marked effect on GPR120 and consequent less efficient ability to reduce inflammation through this pathway. These data point out the importance not only on the type of dietary fatty acids but also on the formulation which may strongly influence their activities in lipid and energy metabolism in the obese by affecting the inflammatory response by targeting GPR120. Future studies should be carried out in larger cohorts and possible modulation of resolvins and protectins biosynthesis should be taken into consideration. In addition, we will aim to evaluate whether in experimental animals and humans the dietary fats by modifying fatty acid profile in different lipid fractions may modulate omega-3 effects, affecting metabolic dysfunction and/or inflammation.