Diet, gut microbiota, TLR4, and obesity.
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ABSTRACT:
PROVIDER: PRJEB26713 | ENA |
REPOSITORIES: ENA
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Project description:Diet induced obesity is independent of metabolic endotoxemia, Tlr4 signalling and hypothalamic inflammation
| PRJEB27397 | ENA
Project description:A number of studies have proposed that excess food intake, particularly of high fat diets arise due dysregulation of homeostatic mechanisms regulating neuroendocrine control of appetite and energy balance. Current dogma suggests high fat diets invoke hypothalamic inflammation which reduces hypothalamic sensitivity to metabolic and hormonal cues of conveying peripheral status of energy balance, such as leptin and insulin. A hypothesis for the mechanism leading to hypothalamic inflammation is based on high fat diet mediated changes in gut microbiota which are then proposed to increase circulating levels of lipopolysaccharide (LPS). This in turn activates a hypothalamic inflammatory response via the toll-like receptor (TLR4) and CD14. The aim of this study was to determine hypothalamic gene expression in response to long term feeding of a high fat diet, taking into account the importance of using a control diet with a similar composition and balanced for sucrose content.
2018-10-23 | E-MTAB-6929 | biostudies-arrayexpress
Project description:Obesity, a prevalent condition in adults and children, impairs bone marrow (BM) function. However, the underlying mechanisms are unclear. Here we show that obese mice exhibit poor emergency immune responses in a toll-like receptor 4 (TLR4)-dependent manner. Canonical myeloid genes (Csf1r, Spi1, Runx1) are enhanced, and lymphoid genes (Flt3, Tcf3, Ebf1) are reduced. Using adoptive transfer and mixed BM chimera approaches we demonstrate that myeloid>lymphoid bias arises after six weeks of high fat diet and depends on precursor cell-autonomous TLR4. Further, lean mice exposed to the TLR4 ligand lipopolysaccharide (LPS) at doses similar to that detectable in obese serum recapitulates BM lympho-myeloid alterations. Together, these results establish a mechanistic contribution of BM cell-intrinsic TLR4 to obesity-driven BM malfunction and demonstrate the importance of LPS. Our findings raises important questions about the impact of maternal obesity and endotoxemia to fetal hematopoiesis, as fetal immune precursors are also sensitive to TLR4 signals.
2018-01-17 | GSE109269 | GEO
Project description:Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists. Using multiple orthogonal approaches, we herein provide evidence that while loss-of-function models confirm that TLR4 does, indeed, regulate lcSFA-induced inflammation, TLR4 is not a receptor for lcSFAs. Rather, we show that TLR4-dependent priming alters gene expression, lipid metabolic pathways, and membrane lipid composition, which are necessary for lcSFA-induced inflammation. These results reconcile previous discordant observations and challenge the prevailing view of TLR4's role in initiating obesity-induced inflammation.
2018-04-22 | GSE100526 | GEO
Project description:G-protein-coupled receptors (GPCRs) represent targets for improved low-side-effect therapies to tackle the evolving Western obesity epidemic. The orphan (o) GPCR GPR101 emerged as an attractive candidate in this regard. Expressed on cells in brain areas regulating energy homeostasis, including the hunger-suppressing proopiomelanocortin (POMC) + neurons, it is minimally expressed outside the brain. To understand the function of this receptor in vivo, we herein generated and comprehensively characterized a Gpr101 knockout mouse line, either under standard feeding conditions or with chronic high-fat diet (HFD) access (16 weeks). GPR101 loss accelerated the risk for diet-induced obesity (DIO), hyperinsulinemia and disrupted glucose homeostasis. Hypothalamic transcriptomic analysis revealed also decreased Pomc activation with HFD suggesting impaired hunger suppression. Moreover, on a standard diet, there was a molecular signature of downregulated tristetrapolin (TTP) pathway gene activation suggesting impaired inflammation resolution and one of aberrant microglial phagocytosis and lipid metabolism on HFD. Morphometry revealed altered hypothalamic arcuate nucleus microglial morphology consistent with the transcriptomic profile. We discuss how the GPR101 specialized pro-resolving mediator (SPM) receptor capacity likely underlies the aberrant microglial function and contributes to DIO risk. Thus, this evidence shows that GPR101 is a potential therapeutic target for DIO through, among other factors, effects on hypothalamic inflammation resolution.
2023-04-18 | GSE220533 | GEO
Project description:Purpose: To profile the transcriptomes of omental adipose tissues from obese and lean humans. Methods: Omental adipose tissues from obese and lean patients were subjected to RNA-Seq. Results: Differential expression analysis identified 206 dysregulated genes (p-value < 0.05 by moderated t-test and fold change M-bM-^IM-% 2 in obesity) that are known to be involved in a multitude of functions, including response to stress, inflammatory response and leukocyte adhesion. Differential splicing analysis uncovered the possible role of TLR4 RNA splicing in obesity. Our findings suggest that, as a person experiences weight gain/obesity, the adipose splicing pattern of TLR4 transcripts changes in favor of activation of TLR4 signaling, which in turn may contribute to the progression of obesity-related inflammation and complications. Conclusion: This study provides a look into the transcriptome of disease-state adipose tissue in obesity, and demonstrates the potential importance of aberrant RNA splicing and expression in obesity-associated immune dysregulation. Study design is of cross-sectional nature. Seven samples (three obese and four lean) were analyzed.
2015-02-11 | E-GEOD-55008 | biostudies-arrayexpress
Project description:Inflammatory immune disorders such as inflammatory bowel disease (IBD) and multiple sclerosis (MS) are major health problems. Currently, the intestinal whipworm Trichuris suis is being explored in clinical trials to reduce inflammation in these diseases, however, the mechanisms by which the parasite affects the host immune system are not known. Here we determined the effects of T. suis soluble products (SPs) on toll-like receptor-4 (TLR4)-stimulated human dendritic cells (DCs) using Illumina bead chip gene arrays. Pathway analysis of lipopolysaccharide (LPS)-stimulated DCs with or without T. suis treatment showed that costimulation with T. suis SPs resulted in a down-regulation of both the myeloid differentiation primary response gene 88 (MyD88)-dependent and the TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent signalling pathways triggered by TLR4. These data were verified using quantitative real-time PCR of several key genes within these pathways and/or defining their protein levels. In addition, T. suis SPs induce Rab7b, a negative regulator of TLR4 signalling that interferes with its trafficking, which coincided with a reduced surface expression of TLR4. These data indicate that the mechanism by which T. suis SPs reduce inflammatory responses is through suppression of both TLR4 signalling and surface expression on DCs.
2015-05-01 | E-MTAB-3443 | biostudies-arrayexpress
Project description:Obesity is an independent risk factor for colorectal cancer (CRC) although the underlying mechanisms have not been elucidated. Dietary nutrients play a key role in both the prevention and promotion of CRC. While iron is an essential nutrient, excess iron is associated with carcinogenesis. Unlike the systemic compartment, the intestinal lumen lacks an efficient system to regulate iron. In conditions when dietary iron malabsorption and intestinal inflammation co-exist, greater luminal iron is associated with increased intestinal inflammation and a shift in the gut microbiota to more pro-inflammatory strains. However, treatments designed to reduce luminal, including diet restriction and chelation, are associated with lower intestinal inflammation and the colonization of protective gut microbes. Obesity is associated with inflammation-induced, hepcidin-mediated, iron metabolism dysfunction characterized by iron deficiency and dietary iron malabsorption. Obesity is also linked to intestinal inflammation. Currently, there is a fundamental gap in understanding how altered iron metabolism impacts CRC risk in obesity.
The investigator’s objective is to conduct a crossover controlled feeding trial of: 1) a "Typical American" diet with "high" heme/non-heme iron", 2) a "Typical American" diet with "low" iron, and 3) a Mediterranean diet with "high" non heme iron and examine effects on colonic and systemic inflammation and the gut microbiome.
| 2274754 | ecrin-mdr-crc
Project description:Purpose: To profile the transcriptomes of omental adipose tissues from obese and lean humans. Methods: Omental adipose tissues from obese and lean patients were subjected to RNA-Seq. Results: Differential expression analysis identified 206 dysregulated genes (p-value < 0.05 by moderated t-test and fold change ≥ 2 in obesity) that are known to be involved in a multitude of functions, including response to stress, inflammatory response and leukocyte adhesion. Differential splicing analysis uncovered the possible role of TLR4 RNA splicing in obesity. Our findings suggest that, as a person experiences weight gain/obesity, the adipose splicing pattern of TLR4 transcripts changes in favor of activation of TLR4 signaling, which in turn may contribute to the progression of obesity-related inflammation and complications. Conclusion: This study provides a look into the transcriptome of disease-state adipose tissue in obesity, and demonstrates the potential importance of aberrant RNA splicing and expression in obesity-associated immune dysregulation.
2015-02-11 | GSE55008 | GEO
Project description:Although there are studies on obesity and sarcopenia, our understanding of obesity-mediated sarcopenia is insufficient. Additionally, no studies have investigated the application of luteolin in sarcopenia. We attempted to determine the effect of luteolin on obese sarcopenia in mice with high-fat diet (HFD)-induced obesity. Luteolin exerted suppressive effects on obesity, inflammation, and protein degradation in HFD-fed obese mice. Luteolin inhibited lipid infiltration into the muscle and decreased p38 and JNK activity and mRNA expression of inflammatory factors, such as TNFα, Tlr2, Tlr4, MCP1, and MMP2, in the muscle. Suppression of muscle inflammation by luteolin led to the inhibition of myostatin, FoxO, atrogin, and MuRF expression, which reduced protein degradation and improved muscle function. This is the first study to demonstrate that luteolin exerts a protective effect against obese sarcopenia, as its anti-obesity and anti-inflammatory activities inhibited protein degradation. Therefore, luteolin may be a useful supplement for prevention of obese sarcopenia.
2022-07-27 | GSE209778 | GEO