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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is becoming one of the most serious public health problems in industrialized societies, due to the profound changes in lifestyle, and notably in nutrition. Beside diabetes, cardiovascular diseases or hypertension, increased susceptibility to infection is one of the pathological consequences of being overweight. In this paper, we have assessed the influence of a high-fat diet (HFD) rich in saturated fatty acids on the immune system of DO11.10 mice, which are transgenic for a T-cell receptor specifically recognizing a peptide of ovalbumin. We showed that the specific T-cell immune response was impaired by high-fat feeding, and that the expression of this defect is different depending on whether T cells are naive or Ag experienced. Indeed, on in vitro ovalbumin stimulation, spleen T cells from naive HFD-fed transgenic mice showed proliferation similar to that of cells from standard diet (SD)-fed mice, but exhibited a strong inflammatory profile as shown by the markedly increased IFN-gamma/IL-4 ratio. Inversely, spleen T cells from ovalbumin-immunized HFD mice were impaired in their Ag-dependent proliferation compared to cells from SD mice. By co-culture experiments, we showed that both T cells and antigen-presenting cells were involved in this impairment. Moreover, in ovalbumin-immunized HFD animals, a trend towards Th2 response was noted, compared to immunized SD mice. This data implies that naive T cells could participate actively in the low-grade systemic inflammation observed in overweight patients. Moreover, the impaired activity of Ag-experienced T cells could have major consequences both in defence against infection and/or in vaccination protocols.
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PMID:Influence of high-fat feeding on both naive and antigen-experienced T-cell immune response in DO10.11 mice. 1703 37

Adiponectin and, especially, its oligomeric complex composition have been suggested to be critical in determining insulin sensitivity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in obesity and associated diseases. Therefore, we investigated the effect of long-term exposure of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, and interferon (IFN)-gamma on total insulin-sensitizing adiponectin secretion and adiponectin complex formation from human adipocytes. In parallel, adipocyte delipidation and leptin production levels were monitored. The present study demonstrates that TNF-alpha, IL-1beta, and IFN-gamma dose and time dependently suppressed total adiponectin secretion within 7 days (60, 70, and 35% reduction respectively). IL-6 was also able to reduce (50%) adiponectin production, although only in combination with exogenous soluble IL-6 receptors (sIL-6R). However, the oligomeric distribution (high, middle, and low molecular weight (HMW) complexes) of secreted adiponectin was not altered by any of these cytokines. All studied pro-inflammatory cytokines resulted in delipidation and reduction of lipid-laden adipocyte numbers. Despite this reduction of lipid-laden adipocytes, TNF-alpha, IL-6/sIL-6R, and IL-1beta stimulated leptin release. Our data indicate that (i) long-term pro-inflammatory cytokine exposure downregulates total adiponectin secretion from delipidizing adipocytes and (ii) pro-inflammatory cytokines are not important regulators of adipocyte-derived adiponectin oligomerization. Hence, their individual contribution to low expression of HMW adiponectin found in insulin-resistant conditions seems unlikely. Furthermore, delipidizing adipocytes and preadipocytes are active leptin producers when stimulated by TNF-alpha, IL-6/sIL-6R, and IL-1beta.
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PMID:Pro-inflammatory delipidizing cytokines reduce adiponectin secretion from human adipocytes without affecting adiponectin oligomerization. 1728 29

Morbid obesity is associated with low-grade systemic inflammation and immune activation. Thereby various pro-inflammatory cytokines like TNF-alpha, IL-1, IL-6, IFN-gamma and hormones, such as leptin are synthesized and released in human adipose tissue. The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is widely distributed in mammals and is inducible preferentially by IFN-gamma. IDO degrades the essential amino acid tryptophan to form N-formyl kynurenine which, depending on cell type and enzymatic repertoires, is subsequently converted to finally form niacin. More recently, it has been proposed that activation of IDO is also critically involved in the regulation of immune responses. In obesity plasma tryptophan concentrations have been shown to be decreased and to be independent of weight reduction or dietary intake. In addition, we previously demonstrated that IDO mediated tryptophan catabolism due to chronic immune activation is the cause for such reduced tryptophan plasma levels in morbidly obese patients compared to lean individuals. Furthermore, these tryptophan metabolic changes may subsequently reduce serotonin production and cause mood disturbances, depression, and impaired satiety ultimately leading to increased caloric uptake and obesity. IDO-mediated tryptophan degradation due to chronic immune activation can therefore be considered as the driving force for food intake. We here review the potential pathogenic links between chronic immune activation and decreased IDO mediated tryptophan and serotonin levels in morbid obesity.
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PMID:Chronic immune activation underlies morbid obesity: is IDO a key player? 1743 Jan 17

Obese individuals often have low plasma adiponectin and concomitant chronic inflammation with a predisposition to metabolic and cardiovascular diseases. The present study reports a novel antiinflammatory action of adiponectin in human monocyte-derived macrophages (MPhi) suppressing T-lymphocyte accumulation in atherogenesis. RNA profiling of lipopolysaccharide-stimulated human MPhi identified CXC chemokine ligands (CXCLs), such as IP-10 (interferon [IFN]-inducible protein 10) (CXCL10), I-TAC (IFN-inducible T-cell alpha chemoattractant) (CXCL11), and Mig (monokine induced by IFN-gamma) (CXCL9), T-lymphocyte chemoattractants associated with atherogenesis, among the top 14 transcripts suppressed by adiponectin. Real-time quantitative RT-PCR and ELISA verified that adiponectin inhibited expression of these chemokines at both the mRNA and protein levels in a concentration-dependent manner. Adiponectin reduced the release by lipopolysaccharide-stimulated MPhi of chemoattractant activity for CXC chemokine receptor 3-transfected (receptor for IP-10, Mig, and I-TAC) lymphocytes. Adiponectin decreased lipopolysaccharide-inducible IP-10 promoter activity in promoter-transfected THP-1 MPhi but did not change IP-10 mRNA stability. In lipopolysaccharide-stimulated MPhi, reduction of IFN-beta by adiponectin preceded inhibition of IP-10 mRNA expression. Immunoblot and chromatin immunoprecipitation analyses demonstrated that adiponectin attenuated activation of the transcription factor IFN regulatory factor 3, involved in the MyD88-independent pathway of Toll-like receptor 4 signaling, and subsequent IFN regulatory factor 3 binding to IFN-beta promoter. In vivo studies further demonstrated that apolipoprotein E/adiponectin double-deficient (apoE-/-APN-/-) mice had increased plasma IP-10 levels, accelerated T-lymphocyte accumulation in atheromata, and augmented atherogenesis compared with apoE single-deficient (apoE-/-APN+/+) mice. This study establishes that low levels of adiponectin associated with obesity, the metabolic syndrome, and diabetes favor T-lymphocyte recruitment and contribute to adaptive immune response during atherogenesis.
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PMID:Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. 1823 40

Guggulsterone has been used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on pancreatic beta cells is unknown. Therefore, in this study, the effect of guggulsterone on IL-1beta- and IFN-gamma-induced beta-cell damage was investigated. Treatment of RINm5F (RIN) rat insulinoma cells with IL-1beta and IFN-gamma induced cell damage, and this damage was well correlated with nitric oxide (NO) and prostaglandin E2 (PGE2) production. However, guggulsterone completely prevented cytokines-mediated cytotoxicity, as well as NO and PGE2 production, and these effects were correlated with reduced levels of the inducible form of NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA and protein expressions. The molecular mechanism by which guggulsterone inhibits iNOS and COX-2 gene expressions appeared to involve the inhibition of NF-kappaB activation. The cytoprotective effects of guggulsterone were also mediated through the suppression of the JAK/STAT pathway. Cells treated with the cytokines downregulated the protein level of SOCS-3, however pretreatment with guggulsterone attenuated this decrease. Additionally, in a second set of experiments in which rat islets were used, the findings regarding the beta-cell protective effects of guggulsterone were essentially the same as those observed when RIN cells were used; guggulsterone prevented cytokines-induced NO and PGE2 production, iNOS and COX-2 expressions, JAK/STAT activation, NF-kappaB activation, downregulation of SOCS-3, and impairment of glucose-stimulated insulin secretion. Collectively, these results suggest that guggulsterone may be used to preserve functional beta-cell mass.
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PMID:Guggulsterone, a plant sterol, inhibits NF-kappaB activation and protects pancreatic beta cells from cytokine toxicity. 1834 24

Obesity with insulin resistance and alcohol are the most frequent causes of steatohepatitis. This work investigates the contribution of bioactive TNF and Th1 type cytokines in a mouse model of steatohepatitis induced by FAT alone or FAT+EtOH and endotoxin. The extent of liver injury and cytokine activation induced by endotoxin in chronic FAT-fed mice, FAT+EtOH-fed mice, or mice fed standard chow were analyzed. Endotoxin administration to either FAT-fed or FAT+EtOH-fed mice increased serum ALT and AST compared to standard chow mice. Immunoreactive TNF was strongly activated by LPS in FAT-fed and FAT+EtOH-fed mice which presented the highest levels, but low levels were found in standard chow mice. In contrast, bioactive TNF was only present in serum of FAT-fed and in particular the highest levels were found in FAT+EtOH-fed mice. Moreover, soluble TNFR2 but not TNFR1 was found in lower amounts in serum of FAT+EtOH-fed mice compared to FAT-fed mice. Steatohepatitis was associated with increased IL-6, IFN-gamma, and iNOS mRNA and proteins. Data show that a moderately FAT diet and low-dose EtOH concur to generate steatohepatitis and TNF liver expression after LPS. In this model, changes in the regulation of TNF are associated with increased expression of IL-6, IFN-gamma, and iNOS.
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PMID:Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. 1872 87

Dietary EPA and DHA modulate immunity and thereby may improve the aberrant immune function in obese states. To determine the effects of feeding fish oil (FO) containing EPA and DHA on splenocyte phospholipid (PL) and lipid-raft fatty acid composition, phenotypes and cytokine production, 14-week-old obese, leptin receptor-deficient JCR:LA-cp rats (cp/cp; n 10) were randomised to one of three nutritionally adequate diets for 3 weeks: control (Ctl, 0 % EPA+DHA); low FO (LFO, 0.8 % (w/w) EPA+DHA); high FO (HFO, 1.4 % (w/w) EPA+DHA). Lean JCR:LA-cp (+/ - or +/+) rats (n 5) were fed the Ctl diet. Obese Ctl rats had a higher proportion of n-3 PUFA in splenocyte PL than lean rats fed the same diet (P < 0.05). The lower n-6:n-3 PUFA ratio of splenocyte PL was consistent with the lower mitogen-stimulated interferon (IFN)-gamma and IL-1beta production by cells from obese rats (P < 0.05). Obese rats fed the FO diet had lower mitogen-stimulated Th1 (IFN-gamma) and Th2 (IL-4) cytokine responses, but IL-2 production (concanavalin A; ConA) did not differ (P < 0.05). The HFO diet was more effective in lowering IL-1beta and increasing IL-10 production (ConA, P < 0.05). This lower IL-1beta production was accompanied by a lower proportion of major histocompatability complex class II-positive cells and a higher incorporation of DHA into lipid rafts. This is the first study to demonstrate impaired responses to mitogen stimulation and altered fatty acid incorporation into the membrane PL of JCR:LA-cp rats. Feeding FO lowered the ex vivo inflammatory response, without altering IL-2 production from ConA-stimulated splenocytes which may occur independent of leptin signalling.
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PMID:Feeding long-chain n-3 polyunsaturated fatty acids to obese leptin receptor-deficient JCR:LA- cp rats modifies immune function and lipid-raft fatty acid composition. 1907 34

Invariant NKT (iNKT) cells recognize lipid antigens presented by CD1d and respond rapidly by killing tumor cells and release cytokines that activate and regulate adaptive immune responses. They are essential for tumor rejection in various mouse models, but clinical trials in humans involving iNKT cells have been less successful, partly due to their rarity in humans compared with mice. Here we describe an accumulation of functional iNKT cells in human omentum, a migratory organ with healing properties. Analysis of 39 omental samples revealed that T cells are the predominant lymphoid cell type and of these, 10% expressed the invariant Valpha24Jalpha18 TCR chain, found on iNKT cells, higher than in any other human organ tested to date. About 15% of omental hematopoietic cells expressed CD1d, compared with 1% in blood (p<0.001). Enriched omental iNKT cells killed CD1d(+) targets and released IFN-gamma and IL-4 upon activation. Omental iNKT-cell frequencies were lower in patients with severe obesity (p=0.005), and with colorectal carcinoma (p=0.004) compared with lean healthy subjects. These data suggest a novel role for the omentum in immune regulation and tumor immunity and identify it as a potential source of iNKT cells for therapeutic use.
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PMID:Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. 1958 13

The Centers for Disease Control and Prevention has suggested that obesity may be an independent risk factor for increased severity of illness from the H1N1 pandemic strain. Memory T cells generated during primary influenza infection target internal proteins common among influenza viruses, making them effective against encounters with heterologous strains. In male, diet-induced obese C57BL/6 mice, a secondary H1N1 influenza challenge following a primary H3N2 infection led to a 25% mortality rate (with no loss of lean controls), 25% increase in lung pathology, failure to regain weight, and 10- to 100-fold higher lung viral titers. Furthermore, mRNA expression for IFN-gamma was >60% less in lungs of obese mice, along with one third the number of influenza-specific CD8(+) T cells producing IFN-gamma postsecondary infection versus lean controls. Memory CD8(+) T cells from obese mice had a >50% reduction in IFN-gamma production when stimulated with influenza-pulsed dendritic cells from lean mice. Thus, the function of influenza-specific memory T cells is significantly reduced and ineffective in lungs of obese mice. The reality of a worldwide obesity epidemic combined with yearly influenza outbreaks and the current pandemic makes it imperative to understand how influenza virus infection behaves differently in an obese host. Moreover, impairment of memory responses has significant implications for vaccine efficacy in an obese population.
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PMID:Diet-induced obesity impairs the T cell memory response to influenza virus infection. 2017 21

The AMPK cascade is a sensor of cellular energy change, which monitors the AMP/ATP ratio to regulate cellular metabolism by restoring ATP levels, but its regulation of neuroinflammation mechanism remains unclear. Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been shown to improve several metabolic disorders, such as obesity and type II diabetes. However, the effect of berberine on neuroinflammatory responses in microglia are poorly understood. This study shows that berberine represses proinflammatory responses through AMP-activated protein kinase (AMPK) activation in BV-2 microglia. Our findings also demonstrate that berberine significantly down-regulates LPS- or interferon (IFN)-gamma-induced nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression in BV-2 microglia cells. Berberine also inhibited LPS- or IFN-gamma-induced nitric oxide production. In addition, berberine effectively inhibited proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 expression. On the other hand, upon various inflammatory stimulus including LPS and IFN-gamma, berberine suppressed the phosphorylated of ERK but not p38 and JNK in BV-2 microglia. AMPK activation is catalyzed by upstream kinases such as LKB1 and Ca2+/calmodulin-dependent protein kinase kinase-II (CaMKK II). Moreover, berberine induced LKB1 (Ser428), CaMKII (Thr286), and AMPK (Thr172) phosphorylation, but not AMPK (Ser485). Furthermore, the inhibitory effect of berberine on iNOS and COX-2 expression was abolished by AMPK inhibition via Compound C, an AMPK inhibitor. Berberine-suppressed ERK phosphorylation was also reversed by Compound C treatment. Our data demonstrate that berberine significantly induces AMPK signaling pathways activation, which is involved in anti-neuroinflammation.
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PMID:Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. 2051 29


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