The regulation of inflammation-related genes after palmitic acid and DHA treatments is not mediated by DNA methylation.

Fatty acids (FAs) are known to participate in body inflammatory responses. In particular, saturated FAs such as palmitic acid (PA) induce inflammatory signals in macrophages, whereas polyunsaturated FAs, including docosahexaenoic acid (DHA), have been related to anti-inflammatory effects. Several studies have suggested a role of fatty acids on DNA methylation, epigenetically regulating gene expression in inflammation processes. Therefore, this study investigated the effect of PA and DHA on the inflammation-related genes on human macrophages. In addition, a second aim was to study the epigenetic mechanism underlying the effect of FAs on the inflammatory response. For these purposes, human acute monocytic leukaemia cells (THP-1) were differentiated into macrophages with 12-O-tetradecanoylphorbol-13-acetate (TPA), followed by an incubation with PA or DHA. At the end of the experiment, mRNA expression, protein secretion, and CpG methylation of the following inflammatory genes were analysed: interleukin 1 beta (IL1B), tumour necrosis factor (TNF), plasminogen activator inhibitor-1 (SERPINE1) and interleukin 18 (IL18). The results showed that the treatment with PA increased IL-18 and TNF-α production. Contrariwise, the supplementation with DHA reduced IL-18, TNF-α and PAI-1 secretion by macrophages. However, the incubation with these fatty acids did not apparently modify the DNA methylation status of the investigated genes in the screened CpG sites. This research reveals that PA induces important pro-inflammatory markers in human macrophages, whereas DHA decreases the inflammatory response. Apparently, DNA methylation is not directly involved in the fatty acid-mediated regulation of the expression of these inflammation-related genes.

DNA methylation markers in obesity, metabolic syndrome, and weight loss.

The fact that not all individuals exposed to the same environmental risk factors develop obesity supports the hypothesis of the existence of underlying genetic and epigenetic elements. There is suggestive evidence that environmental stimuli, such as dietary pattern, particularly during pregnancy and early life, but also in adult life, can induce changes in DNA methylation predisposing to obesity and related comorbidities. In this context, the DNA methylation marks of each individual have emerged not only as a promising tool for the prediction, screening, diagnosis, and prognosis of obesity and metabolic syndrome features, but also for the improvement of weight loss therapies in the context of precision nutrition. The main objectives in this field are to understand the mechanisms involved in transgenerational epigenetic inheritance, and featuring the nutritional and lifestyle factors implicated in the epigenetic modifications. Likewise, DNA methylation modulation caused by diet and environment may be a target for newer therapeutic strategies concerning the prevention and treatment of metabolic diseases.

Folic Acid Improves the Inflammatory Response in LPS-Activated THP-1 Macrophages.

DNA methylation has been suggested as a regulatory mechanism behind some inflammatory processes. The physiological actions of methyl donors, such as folic acid, choline, and vitamin B12 on inflammation-related disease have been associated with the synthesis of the universal methyl donor S-adenosyl methionine (SAM). The aim of this study was to evaluate the effects of folic acid, choline, vitamin B12, and a combination of all on preventing the lipopolysaccharide- (LPS-) induced inflammatory response in human THP-1 monocyte/macrophage cells. Folic acid and the mixture of methyl donors reduced interleukin 1 beta (IL1B) and tumour necrosis factor (TNF) expression as well as protein secretion by these cells. Folic acid and choline decreased C-C motif chemokine ligand 2 (CCL2) mRNA levels. In addition to this, the methyl donor mixture reduced Cluster of differentiation 40 (CD40) expression, but increased serpin family E member 1 (SERPINE1) expression. All methyl donors increased methylation levels in CpGs located in IL1B, SERPINE1, and interleukin 18 (IL18) genes. However, TNF methylation was not modified. After treatment with folic acid and the methyl donor mixture, ChIP analysis showed no change in the binding affinity of nuclear factor-κB (NF-κB) to IL1B and TNF promoter regions after the treatment with folic acid and the methyl donor mixture. The findings of this study suggest that folic acid might contribute to the control of chronic inflammation in inflammatory-related disease.

Effects of exosomes from LPS-activated macrophages on adipocyte gene expression, differentiation, and insulin-dependent glucose uptake.

Obesity is usually associated with low-grade inflammation, which determines the appearance of comorbidities like atherosclerosis and insulin resistance. Infiltrated macrophages in adipose tissue are partly responsible of this inflammatory condition. Numerous studies point to the existence of close intercommunication between macrophages and adipocytes and pay particular attention to the proinflammatory cytokines released by both cell types. However, it has been recently described that in both, circulation and tissue level, there are extracellular vesicles (including microvesicles and exosomes) containing miRNAs, mRNAs, and proteins that can influence the inflammatory response. The objective of the present research is to investigate the effect of exosomes released by lipopolysaccharide (LPS)-activated macrophages on gene expression and cell metabolism of adipocytes, focusing on the differential exosomal miRNA pattern between LPS- and non-activated macrophages. The results show that the exosomes secreted by the macrophages do not influence the preadipocyte-to-adipocyte differentiation process, fat storage, and insulin-mediated glucose uptake in adipocytes. However, exosomes induce changes in adipocyte gene expression depending on their origin (LPS- or non-activated macrophages), including genes such as CXCL5, SOD, TNFAIP3, C3, and CD34. Some of the pathways or metabolic processes upregulated by exosomes from LPS-activated macrophages are related to inflammation (complement activation, regulation of reactive oxygen species, migration and activation of leukocyte, and monocyte chemotaxis), carbohydrate catabolism, and cell activation. miR-530, chr9_22532, and chr16_34840 are more abundant in exosomes from LPS-activated macrophages, whereas miR-127, miR-143, and miR-486 are more abundant in those secreted by non-activated macrophages.