Obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. We have provided in vitro evidence that saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for Toll-like receptor 4 (TLR4) to induce the inflammatory changes in macrophages. Here we show the attenuation of adipose tissue inflammation in C3H/HeJ mice carrying a functional mutation in the TLR4 gene relative to control C3H/HeN mice during a 16-week high-fat diet. We also find that adiponectin mRNA expression is significantly reduced by co-culture of hypertrophied 3T3-L1 adipocytes and C3H/HeN peritoneal macrophages, which is reversed, when co-cultured with C3H/HeJ peritoneal macrophages. This study provides in vivo evidence that TLR4 plays a role in obesity-related adipose tissue inflammation and thus helps to identify the therapeutic targets that may reduce obesity-induced inflammation and the metabolic syndrome.
"The SFA (rich in palmitate) expands WAT and increases inflammation and apoptosis through oxidative or endoplasmic reticulum stress, generation of ceramide and reactive oxygen species, and protein kinase C signaling . Additionally, palmitate increases the expression and secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-10   and activates toll-like receptor (TLR) signaling in murine adipocytes    and macrophages    , leading to nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation and cytokine production. Davis et al. showed that TLR4 knockout mice were protected against the adverse effects of eating an HF diet rich in palmitate . "
[Show abstract][Hide abstract] ABSTRACT: During pregnancy and/or lactation, maternal nutrition is related to the adequate development of the fetus, new-born and future adult, likely by modifications in fetal programming and epigenetic regulation. Fetal programming is characterised by adaptive responses to specific environmental conditions during early life stages, which may alter gene expression and permanently affect the structure and function of several organs and tissues, thus influencing the susceptibility to metabolic disorders. Regarding lipid metabolism during the first two trimesters of pregnancy, the maternal body accumulates fat, whereas in late pregnancy, the lipolytic activity in the maternal adipose tissue is increased. However, an excess or deficiency of certain fatty acids may lead to adverse consequences to the fetuses and new-borns. Fetal exposure to trans fatty acids appears to promote early deleterious effects in the offspring’s health, thereby increasing the individual risk for developing metabolic diseases throughout life. Similarly, the maternal intake of saturated fatty acids seems to trigger alterations in the liver and adipose tissue function associated with insulin resistance and diabetes. The polyunsaturated fatty acids (PUFA), particularly long chain PUFA (LC-PUFA-AA, EPA and DHA), play an important and beneficial physiologic role in the offspring who receive this fatty acid during critical periods of development. Therefore, the maternal nutritional condition and fatty acid intake during pregnancy and/or lactation are critical factors that are strongly associated with normal fetal and postnatal development, which influence the modifications in fetal programming and in the individual risk for developing metabolic diseases throughout life.
The Journal of Nutritional Biochemistry 10/2014; 26(2). DOI:10.1016/j.jnutbio.2014.10.001 · 3.79 Impact Factor
"After injury or stimulation, the endogenous ligands increase, and IL-1R/TLR recruits the adaptor molecule myeloid differentiation factor 88 (MyD88) to their TIR domain, transducing more signaling in the cells. Disruption of the TLR4 gene in mice confers protection from obesity-induced inflammation and insulin resistance , . In our carotid balloon injury and LPS stimulation BMM, western blotting and qRT-PCR showed long-lasting expression of TLR4, which confirm the inflammatory process and are consistent with c-Myc, EMR1 and PCNA levels. "
[Show abstract][Hide abstract] ABSTRACT: The value of restenosis after percutaneous coronary intervention (PCI) is recognized worldwide, especially for diabetic patients. Interleukin-1/Toll-like receptor (IL-1/TLR) signaling is involved in innate and adaptive immune responses, but whether and how the IL-1/TLR-induced nuclear factor kappa B (NFκB) pathway plays key roles in intimal formation is unclear. The underlying mechanism of intima hyperplasia was investigated with a model of carotid balloon injury in Goto-Kakizaki (GK) and Wistar rats and with lipopolysaccharide-stimulated macrophages. Elastic-van Gieson staining showed the medial area peakedon Day 3 post-injury and decreased by Day 7 post-injury in both GK and Wistar rats. The N/M at Day 7 in GK rats was significantly higher than in Wistar rats (p<0.001). The percent of 5-ethynyl-2'-deoxyuridine (EdU) staining-positive cells on Day 3 post-injury was greater than seen on Day 7 post-injury in GK and Wistar rats. The percent of EdU-positive cells on Days 3 and 7 post-injury in Wistar rats was less than that found in GK rats (p<0.01; p<0.05). NFκBp65 immunostaining had increased by Day 7 post-injury. Agilent Whole Genome Oligo Microarray verified that the IL-1/TLR-induced NFκB pathway was activated by carotid balloon injury. TLR4, IL-1 receptor associated kinase, inhibitors α of NFκB, human antigen R, c-Myc (Proto-Oncogene Proteins), EGF-like module-containing mucin-like hormone receptor-like 1 and Interleukin-6 were up-regulated or down-regulated according to immunochemistry, quantitative real-time PCR, Western blotting and Enzyme linked immunosorbent assay. Overall, we conclude that the IL-1/TLR-induced NFκB pathway participates in the intimal hyperplasia after carotid injury in GK and Wistar rats and that GK rats respond more intensely to the inflammation than Wistar rats.
PLoS ONE 08/2014; 9(8):e103794. DOI:10.1371/journal.pone.0103794 · 3.23 Impact Factor
"Insulin resistance was estimated using the homeostasis model assessment (HOMA- IR) as described by Matthews et al.  and validated by several authors for epidemiological studies . HOMA-IR was calculated as the product of fasting glucose (mmol/L) and fasting insulin (mU/L) divided by 22.5. "
[Show abstract][Hide abstract] ABSTRACT: T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication's prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (P = 0.026), lower limb arteriopathy (P = 0.013), and the major cardiovascular pathologies (P = 0.017). Their cumulative risk was significant (P = 0.01), with a threefold risk to develop neuropathy, lower limb arteriopathy, and major cardiovascular events in AG cases compared to AA cases. The adjusted OR for the confounding variables was 3.788 (95% CI: 1.642-8.741). Thus, the rs4986790 polymorphism may be an indicative of prevalence of complications in T2DM patients.
Mediators of Inflammation 04/2014; 2014:973139. DOI:10.1155/2014/973139 · 3.24 Impact Factor
Alexandra Mangili, Julian Falutz, Jean-Claude Mamputu, Miganush Stepanians, Brooke Hayward
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