Proposal of a bioinformatics approach to predict molecular mechanisms involved in inflammatory response: case of ATRA and 1,25(OH) ₂ D in adipocytes

Abstract

Several inflammatory markers such as cytokines, chemokines, and microRNAs (miRNAs) are well known to be induced during obesity and are strongly linked to their comorbidities. Among many others factors, the micronutrient status is suspected to reduce obesity-associated inflammation via blunting inflammatory signalling pathways. This is notably the case for active forms of vitamin A (all-trans retinoic acid ATRA) and vitamin D (1,25(OH) 2 D) as previously shown. In the present study, we aimed to implement a new bioinformatics approach to unveil commonly regulated signalling pathways through a combination of gene and miRNA expression sets impacted by ATRA and 1,25(OH) 2 D in adipocytes. In a first set of experiments, we focused only our attention on ATRA and demonstrated that it reduced LPS-mediated miRNA expression (miR-146a, miR-150, and miR-155) in mouse adipose tissue, in adipocyte cultures, and in adipocyte-derived vesicles. This result was confirmed in TNFα-induced miRNA in human adipocytes. Then, bioinformatic analysis highlighted that both ATRA and 1,25(OH) 2 D-regulated genes and miRNA converge to the canonical ‘nuclear factor Kappa B (NF-κB) signalling pathway.’ Altogether, these results showed that ATRA has anti-inflammatory effects on miRNA expression. In addition, the proposed bioinformatic model converges to NF-κB signalling pathway that has been previously demonstrated to be regulated by ATRA and 1,25(OH) 2 D, thus confirming the interest of such approach.

From the Sun to the Cell: Examining Obesity through the Lens of Vitamin D and Inflammation

“…The activation of the NF-κB signaling pathway was associated with the obesity index, as well as with genomic and epigenetic profiles [ 110 ]. A recent study [ 111 ] combining animal experiments and bioinformatics analyses showed that 1,25(OH) 2 D 3 upregulated 45 mRNAs and putative target miRs and increased the activity of 87 related pathways. Furthermore, bioinformatics analysis revealed that the genes regulated by 1,25(OH) 2 D 3 and their target miRs converged on the classical NF-κB signaling pathway.…”

Aging alone or combined with obesity increases white adipose tissue inflammatory status in male mice

“…Several studies have shown inflammation during obesity or aging-induced miRNA expression, notably in WAT and adipocytes 6 , 8 , 9 , 18 , 20 . Thus, we assessed the expression of an inflammatory miRNA panel in WAT and generated a heatmap with the miRNAs exhibiting statistically significant changes.…”

“…This result could be explained by the presence of miR-155 in this cluster, which was involved in inflammatory pathways 6 , 18 . Indeed, studies have demonstrated an upregulation of miR-155 in response to inflammatory stimulations during aging and obesity 20 , 61 . Such induction of miR-155 in our experimental conditions could vigorously participate in adipose tissue inflammation.…”

“…These miRNAs, including miR-221 and miR-222, targeted the NF-κB signaling, which is a crucial mediator of obesity-related inflammation 58 – 60 . Moreover, among affected pathways, several nuclear receptors signaling were impacted, notably the vitamin D receptor (VDR/RXR) signaling, which could participate in the increased adipose tissue inflammation 14 , 18 , 20 , 24 . The fifth cluster appeared to follow the mRNA expression patterns of cytokines in WAT, with miRNAs being upregulated during obesity and aging, mainly in the combined effect of both.…”