Castilla-Madrigal, R. M. (Rosa María)

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    La citoquina pro-inflamatoria TNF-alfa reduce el transporte intestinal de azúcar: su relación con obesidad y el efecto bloqueante del EPA, DHA y mediadores lipídicos pro-resolutivos derivados del DHA
    (2018-04-16) Castilla-Madrigal, R. M. (Rosa María); Lostao, M.P. (María Pilar)
    Tumor necrosis factor alfa (TNF-α) is a pro-inflammatory cytokine that acts in an autocrine and paracrine way by binding to its receptors TNFR1 and TNFR2. This cytokine is implicated in numerous diseases with an inflammatory component, as inflammatory bowel disease (IBD). Obesity is a low grade chronic inflammatory state that could contribute to the chronic intestinal inflammation in IBD. Also, high amounts of TNF-α have been found during obesity. During the triggering of intestinal inflammation different mediators induce the switch of tissue-resident M2 macrophages into pro-inflammatory M1 macrophages, and M1 macrophages infiltration. In turn, M1 macrophages secrete pro-inflammatory cytokines including TNF-α. Obesity would impact the intestinal function through the recruitment and activation of macrophages. Omega-3 polyunsaturated fatty acids (n3-PUFAs) and its derived lipid mediators show anti-inflammatory actions on inflammatory-related pathologies, including intestinal inflammation. In enterocytes, glucose is actively transported by the Na+/glucose cotransporter SGLT1. Glutamine, an essential amino acid for the maintenance of the gut barrier function and the intestinal cell proliferation, is mainly transported by the Na+- dependent glutamine transporter B0AT1. We have previously demonstrated, in the human intestinal epithelial cell line Caco-2, that TNF-α inhibits αMG uptake by decreasing SGLT1 expression in the brush border membrane. The goal of this study was to investigate the double hypothesis: 1) That n-3 PUFAs and DHA derived specialized pro-resolving lipid mediators (MaR1, RvD1 and RvD2) can counteract TNF-α-induced inhibition of nutrients intestinal transport, acting from the apical membrane of the enterocytes. 2) That basolateral TNF-α, in relation with obesity, can inhibit nutrients transport and induce its own expression in the enterocytes. This research demonstrates that, after pre-incubation of the Caco-2 cells with apical TNF-α and EPA, EPA prevented the inhibitory effect of the cytokine on α-methyl- D-glucose (αMG) uptake and on SGLT1 expression at the brush border membrane, measured by Western blot. The ERK1/2 inhibitor PD98059 and the AMPK activator AICAR also prevented the inhibitory effect of TNF-α on both αMG uptake and SGLT1 expression. Interestingly, the AMPK inhibitor, Compound C, abolished the ability of EPA to prevent TNF-α-induced reduction of sugar uptake and transporter expression. The GPR120 antagonist, AH7614, also blocked the preventive effect of EPA on TNF-α- induced a decrease of αMG uptake and AMPK phosphorylation. Moreover, DHA blocked apical TNF-α-induced inhibition of αMG uptake and SGLT1 expression in the apical membrane, through a pathway which seemed to be independent of GPR120. MaR1, RvD1 and RvD2 showed the same preventive effect on TNF-α action, but acting at concentration 1,000 times lower. TNF-α also inhibited glutamine (Gln) uptake in Caco-2 cells being this inhibition also blunted by EPA, DHA and the DHA-SPMs. Interestingly, TNF-α increased the expression in the membrane of the glutamine transporter B0AT1. This increase was partially avoided by the omega-3 fatty acids. These data present DHA and its specialized pro-resolving lipid mediators as promising biomolecules to restore intestinal nutrients transport during intestinal inflammation. On the other hand, TNF-α and the secretions from overweight adipocytes (hMSCDA) and macrophages (inactive and active), acting from the basolateral membrane of Caco-2 cells, decrease sugar uptake. In Caco-2 cell under basolateral TNF-α stimulation and in overweight hMSC-DA, there is up-regulation of TNF-α, IL-1β and MCP1 gene expression. To approach our in vitro results to the in vivo model, we used diet induced obese (DIO) mice. In DIO mice, αMG intestinal transport and SGLT1 expression in the brush border membrane was lower than in lean animals. This effect was accompanied by an increase on Tnf-α, Il-1β and Il-6 gene expression in the jejunal mucosa. Oral administration of MaR1 reversed the up-regulation of the pro-inflammatory cytokines found in the DIO intestinal mucosa, but not the decrease on sugar uptake or SGLT1 amount in the brush border membrane. In conclusion, the results of this work support that TNF-α secreted by the small intestine, macrophages and adipocytes during intestinal inflammation and obesity can decrease sugar and glutamine absorption. They also support that the omega-3 EPA, DHA and the DHA derived pro-resolving lipid mediators are able to block TNF-α effect- This suggest that EPA, DHA and DHA-SPMs could be beneficial biomolecules to restore intestinal nutrients transport in patients suffering intestinal inflammation.
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    Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice
    (Wiley, 2021) Collantes, M. (María); Moreno-Aliaga, M. J. (María Jesús); Gil-Iturbe, E. (Eva); Dalli, J. (Jesmond); Félix-Soriano, E. (Elisa); Fernandez-Galilea, M. (Marta); Castilla-Madrigal, R. M. (Rosa María); Sainz, N. (Neira); Ly, L. (Lucy)
    Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2-and 18-month- old lean (CT) female mice and in 18-month- old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)-derived LXs and DHA-derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice.Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged mice included LXB4, MaR2, 4S,14S-diHDHA, 10S,17S-diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA-derived SPMs, without modifying LXs. However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese-aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese-aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.