Sa1688 Multiple Functional Roles for the Extracellular Matrix Glycoprotein Tenascin X

in two HFD murine models.Methods: Plasma LPS and nitrergic myenteric neurons quantification in the proximal colon were assessed in HFD mice (60% cal from fat) and in Westerndiet mice (WD, 35% cal from fat) after 12 weeks of feeding.Cultured enteric neurons were incubated for 24h with LPS and/or palmitate.The importance of the TLR4 signaling was confirmed in culture with an antagonist (LPS-RS) and also in vivo in TLR4-/-mice where nitrergic myenteric cell loss was investigated after 12 weeks of WD.Data are presented as mean ± SEM and significant to p<0.05.Results: Mice exposed to HFD for 12 weeks lost 37% of neurons (RD: 50.45 ± 2.48 neurons/field; HFD: 31.75 ± 1.46) whereas this loss was 51% in WD mice (RD: 37.23 ± 2.06 neurons/field; WD: 18.5 ± 3.20).Plasma LPS levels were increased in HFD mice compared to regularly-fed animals (RD: 0.05 ± 0.01 ng/ ml; HFD: 0.15 ± 0.03), however no alteration was observed in WD mice and their respective controls (RD: 0.08 ± 0.01 ng/ml in both groups).Incubations with LPS (0.5, 1, 1.5 and 2 ng/ml) did not induce enteric cell loss in vitro, however the addition of palmitate (0.04 mM) initiated this phenomenon which was abolished in presence of LPS-RS (20 ng/ml).Finally TLR4-/-mice did not exhibit myenteric cell loss after 12 weeks of WD feeding (RD: 25.30 ± 4.24 neurons/field; WD: 28.50 ± 4.035).Conclusion: Our results show that WD-induced nitrergic myenteric cell loss is TLR4-mediated and requires the synergic action of LPS and plasma palmitate, suggesting that saturated fatty acids initiate LPS neurotoxic action at the level of the enteric nervous system.This nitrergic myenteric neuronal loss in the proximal colon contributes to the delayed colonic transit observed in WD-fed animals.