Project description:When macrophages are activated by sensing bacterial lipopolysaccharides (LPS), they greatly increase their motility, mRNA synthesis and protein production. Most of the ATP needed for these responses is derived from the uptake and catabolism of glucose, a relatively inefficient ATP source. Although the stimulated cells also increase their uptake of free fatty acids, they store a large fraction as triglycerides (TAG). We report here that both Toll-like receptor 4 (TLR4) and TLR2 agonists stimulate prolonged TAG retention by primary murine and human macrophages. Agonist-induced TAG storage lasted at least 72-96 hrs in vitro and was associated with increases in fatty acid (FA) uptake, FA esterification, and FA incorporation into TAG; FA oxidation decreased. The results of expression and inhibitor studies support a prominent role for increases in long chain acyl CoA synthase 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2) during the sustained response to TLR2/4 activation; decreases in adipose triglyceride lipase (ATGL, Pnpla2) and monoacylglycerol lipase (MgII) may also contribute. Stimulated murine macrophages that retained TAG carried out phagocytosis more effectively and were protected from saturated fatty acid-induced cell death (lipotoxicity). TLR agonist-induced TAG retention in macrophages is thus an active, sustained process that may have important adaptive functions. It may also contribute to the persistence of lipid-laden macrophages in infected tissues, host susceptibility to some microbial pathogens, and the pathogenesis of atherosclerosis. RNA from macrophage loaded with Fatty Acids, stimulated with bacterial lipopolysaccharides (LPS), or both compared to untreated controls (FA, LPS, FA+LPS, untreated). Replicates from 4 independent experiments.
Project description:Necroptosis is a caspase-independent form of regulated cell death that is characterized by membrane permeabilization and rupture. This membrane rupture is responsible for the inflammatory properties of necroptosis and is critical for disease states involving this process. In efforts to understand how lipids might contribute to necroptosis, we previously showed that saturated very long chain fatty acids (VLCFAs) are functionally involved in this process, potentially through protein fatty acylation. Here we define the scope of protein acylation by saturated VLCFAs during necroptosis using a clickable lipid analog and IonStar quantitative proteomics.As a result, a total of 1672 proteins were quantified with high precision and no missing data across samples in the same condition. 1267 were detected with higher abundances in control cells and 405 were detected with higher abundance in necroptotic conditions.
Project description:When macrophages are activated by sensing bacterial lipopolysaccharides (LPS), they greatly increase their motility, mRNA synthesis and protein production. Most of the ATP needed for these responses is derived from the uptake and catabolism of glucose, a relatively inefficient ATP source. Although the stimulated cells also increase their uptake of free fatty acids, they store a large fraction as triglycerides (TAG). We report here that both Toll-like receptor 4 (TLR4) and TLR2 agonists stimulate prolonged TAG retention by primary murine and human macrophages. Agonist-induced TAG storage lasted at least 72-96 hrs in vitro and was associated with increases in fatty acid (FA) uptake, FA esterification, and FA incorporation into TAG; FA oxidation decreased. The results of expression and inhibitor studies support a prominent role for increases in long chain acyl CoA synthase 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2) during the sustained response to TLR2/4 activation; decreases in adipose triglyceride lipase (ATGL, Pnpla2) and monoacylglycerol lipase (MgII) may also contribute. Stimulated murine macrophages that retained TAG carried out phagocytosis more effectively and were protected from saturated fatty acid-induced cell death (lipotoxicity). TLR agonist-induced TAG retention in macrophages is thus an active, sustained process that may have important adaptive functions. It may also contribute to the persistence of lipid-laden macrophages in infected tissues, host susceptibility to some microbial pathogens, and the pathogenesis of atherosclerosis.
Project description:Disruption of circadian rhythm during pregnancy produced adverse health outcomes in offspring. However, the role of maternal circadian rhythms in infants’ immunity and their susceptibility to inflammation remains poorly understood. Here we reported that disruption of circadian rhythms in pregnant mice profoundly aggravated the severity of neonatal inflammatory disorders, including necrotizing enterocolitis (NEC) and sepsis. The diminished production of maternal-derived docosahexaenoic acid (DHA) and the impaired immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in neonates played a dominant role in this process. Mechanistically, DHA enhanced the immunosuppressive function of neonatal MDSCs viaPPARγ mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieved neonatal inflammation induced by maternal rhythms disruption. These observations revealed an important role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.
Project description:Disruption of circadian rhythm during pregnancy produced adverse health outcomes in offspring. However, the role of maternal circadian rhythms in infants’ immunity and their susceptibility to inflammation remains poorly understood. Here we reported that disruption of circadian rhythms in pregnant mice profoundly aggravated the severity of neonatal inflammatory disorders, including necrotizing enterocolitis (NEC) and sepsis. The diminished production of maternal-derived docosahexaenoic acid (DHA) and the impaired immunosuppressive function of myeloid-derived suppressor cells (MDSCs) in neonates played a dominant role in this process. Mechanistically, DHA enhanced the immunosuppressive function of neonatal MDSCs viaPPARγ mediated mitochondrial oxidative phosphorylation. Transfer of MDSCs or perinatal supplementation of DHA relieved neonatal inflammation induced by maternal rhythms disruption. These observations revealed an important role of maternal circadian rhythms in the control of neonatal inflammation via metabolic reprograming of myeloid cells.
Project description:Our study demonstrates that the short-chain fatty acid, butyrate, greatly enhances the in utero development of ENCSCs and adult enteric neurogenesis, which was partially mediated through the receptors MCT1 and Ras signaling pathway. In conclusion, butyrate treatment may represent a potential therapy for various gastrointestinal motility disorders.
Project description:Maternal body size, nutrition, and hyperglycemia contribute to neonatal body size and composition. There is little information on maternal-fetal transmission of messages which influence fetal growth. We analyzed adipocyte-derived small extracellular vesicular (ADsEV) microRNAs in maternal and cord blood to explore their adipogenic potential. Differential expression (DE) of ADsEV miRNAs in adipose vs. lean neonates was studied before and after adjustment for maternal gestational diabetes mellitus (GDM), adiposity, and vitamin B12-folate status.
Project description:The omega-3 long chain poly-unsaturated fatty acid (n-3 LCPUFA) docosahexaenoic acid (DHA) plays a central role in fetal and neonatal development in humans, in particular the development of the brain and nervous system, and this has led to numerous studies focussed on determining the effect of exposure to an increased supply of DHA on pregnancy and neonatal outcomes. The aim of this study was to determine the impact of treatment with a DHA-enriched fish-oil emulsion on fatty acid composition, proliferation rate and gene expression in human placental HTR8/SVneo cells in vitro.
Project description:Feed additives aiming to improve gastrointestinal health are frequently supplied to piglets after weaning but might be more effective when administered before weaning. In this period, feed additives can either be administered directly to neonates, or indirectly via sow’s feed. It is yet unknown what the effect of the administration route is on gut functionality and health. Therefore, we compared the effect of different dietary interventions on gut functionality after maternal administration (lactation feed) to the neonatal administration route (oral gavage). These feed interventions included medium chain fatty acids (MCFA), beta-glucans (BG), and galacto-oligosaccharides (GOS). We measured intestinal gene expression and microbiota composition after birth (d1) and after weaning (d31). Our results show that the type of intervention and the administration route influence gut functionality (microbiome and gene expression profiles). MCFA administration led to a more differentially orchestrated response when comparing the neonatal and maternal administration route then the other two additives, indicating the route of administration of the feed interventions is determinative for the outcome. This implies that for each nutritional intervention in early life of a pig the optimal route of administration needs to be determined.
Project description:The beneficial effects of dietary long-chain (LC) n-3 polyunsaturated fatty acids (PUFA) in the prevention and/or treatment of some metabolic disorders result largely from their capacity to regulate the transcription level of many genes involved in metabolic and physiological homeostasis, especially in the liver. In this respect, they are known to bind and activate the Peroxisome Proliferator-Activated Receptor alpha (PPARalpha). The precursor of LC-PUFA, a-linoleic acid (ALA, C18:3 n-3) share some beneficial metabolic effects with its LC derivatives, however its role in gene regulation is poorly documented. Here, we analysed the hepatic transcriptome of mice fed for 5 weeks diets rich in either saturated FA from palm oil (PALM group) or ALA from linseed oil (LIN group). This modification of dietary fatty acid composition in a context of a high fat diet had a subtle but significant effect on the hepatic transcriptome. We identified mainly a group of genes that were upregulated in the LIN vs the PALM group and that include several well-known PPARalpha target genes involved in lipid and xenobiotic metabolism. Liver gene expression was measured in male C57BL/6J mice fed during 5 weeks a high fat diet (51% energy from fat) containing palm oil, rich in saturated fatty acids (n=10) or linseed oil, rich in 18:3 n-3 (n=8)