Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immune activation occurs in response to noxious stimuli such tissue injury, infection, inflammation and malignant neoplasia with the production of cytokines both in the circulation and the central nervous system (CNS). In addition to their fundamental immune functions, cytokines such as the interleukins (ILs), interferons (IFNs) and tumour necrosis factor-alpha also elicit significant pathophysiological effects on feeding behaviour and play prominent roles in the anorexia and cachexia syndrome often seen in chronic disease states. There is now compelling evidence that demonstrates that an important site of cytokine bioactivity is located within the hypothalamus where they appear to modulate appetite and energy homeostasis. Hypercytokinaemia has also been observed in the obese state where it has been proposed that they may play pivotal roles in mediating the detrimental components of the metabolic syndrome including insulin resistance, impaired glucose tolerance, hypertension. dyslipidaemia and increased cardiovascular risk. This review summarises these putative roles of various cytokines in the regulation of feeding in the setting of anorexia-cachexia and obesity.
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PMID:Role of cytokines in regulating feeding behaviour. 1505 11

This study was performed to compare concentrations of pro-inflammatory cytokines, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) as well as acute-phase protein, such as C-reactive protein (CRP) between subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). The purpose of this study was to verify whether the pro-inflammatory cytokine-induced acute-phase response is a pathogenic mechanism in type 2 diabetes in elderly Korean women. A total of 1737 elderly subjects aged over 60 years participated in a population based study in Seoul, Korea (SWS Study 1999). Amongst them, a total of 232 non-smoking and non-diabetic female subjects aged 60-89 years was randomly selected and compared with each other. Higher serum high-sensitivity CRP (hs-CRP) concentrations were shown in subjects with IGT than those with normal glucose tolerance (median 1.2 versus 0.9, P < 0.05). Moreover, a relationship between serum hs-CRP concentrations and many components of the metabolic syndrome were detected. Serum pro-inflammatory cytokine IL-6 or TNF-alpha concentrations, however, were neither increased in subjects with IGT nor closely correlated with the components of the metabolic syndrome. In multiple regression analysis with stepwise selection method using hs-CRP as a dependent variable, it was found that white blood cell (WBC) counts, body mass index (BMI), fasting insulin, post-load 2h glucose, hematocrit and LDL cholesterol were significant independent variables. Our study confirms that increased acute-phase reaction is associated with impaired glucose tolerance and the metabolic syndrome in elderly Korean women. However, the hypothesis that pro-inflammatory cytokine-induced systemic inflammation is an early metabolic defect prior to onset of type 2 diabetes, is not supported in our study of elderly Korean women.
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PMID:Comparison of serum concentrations of C-reactive protein, TNF-alpha, and interleukin 6 between elderly Korean women with normal and impaired glucose tolerance. 1506 2

The emergence of a new metabolic syndrome in patients with HIV infection, termed "HIV-associated dyslipidemic lipodystrophy" (HADL), is characterized by central fat redistribution, severe dyslipidemia, and insulin resistance and predisposes to an increased risk of cardiovascular disease. The factors promoting the development of cardiovascular disease in this condition are not well understood and may involve contributions from antiretroviral drugs and components of the HIV virus, as well as inflammatory cytokines, leading to accelerated lipolysis, dyslipidemia, lipotoxic insulin resistance, and vascular inflammation. In this article, we review HADL in terms of metabolic, molecular, and cytokine derangements leading to cardiovascular disease.
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PMID:Cardiovascular implications of HIV-associated dyslipidemic lipodystrophy. 1506 41

Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.
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PMID:Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. 1524 Aug 80

Tumor necrosis factor-alpha (TNF-alpha) seems to be increased in obese subjects, suggesting its role as a proinflammatory cytokine to insulin resistance and metabolic abnormalities in obesity. The aim of this study was to evaluate the relationship between serum TNF-alpha, soluble TNF-alpha receptor 1 (sTNF-R1), TNF-alpha receptor 2 (sTNF-R2), and metabolic syndrome (MS) components and anthropometric indices in obese and non-obese adolescents. A cross-sectional study was performed on obese and non-obese adolescents. We studied 71 adolescents (age, 15 to 16 years old); 39 were obese (obese group; 14 males and 25 females) and 32 were non-obese adolescents (non-obese lean group; 12 males and 20 females). The body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were determined in each subject. The serum TNF-alpha, sTNF-R1, sTNF-R2, fasting plasma glucose (FPG), and lipid profile were also measured. The mean serum TNF-alpha, sTNF-R1, and sTNF-R2 were significantly higher in the obese than the non-obese group (TNF-alpha, 18.15 v 5.88 pg/mL, P < .001; sTNF-R1, 2.01 v 1.40 ng/mL, P < .001; sTNF-R2, 6.06 v 3.70 pg/mL, P < .001). The serum TNF-alpha concentrations were positively correlated with the BMI (TNF-alpha, r = 0.346, P < .05; sTNF-R1, r = 0.624, P < .001; sTNF-R2, r = 0.482, P < .001, respectively) and WC (TNF-alpha, r = 0.525, P < .05; sTNF-R1, r = 0.700, P < .001; sTNF-R2, r = 0.669, P < .001, respectively). The serum TNF-alpha was positively correlated with triglyceride (TG) and DBP, and negatively with high-density lipoprotein-cholesterol (HDLC). The sTNF-R1 and sTNF-R2 were correlated with TG and DBP, and TG, respectively. Obese compared with non-obese adolescents exhibited higher concentrations of TNF-alpha and its soluble receptors, and the higher TNF-alpha concentrations were associated with several components of MS in obese adolescents.
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PMID:Serum tumor necrosis factor-alpha levels and components of the metabolic syndrome in obese adolescents. 1525 78

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name 'adipocytokines' or 'adipokines'. However, since most are neither 'cytokines' nor 'cytokine-like', it is recommended that the term 'adipokine' be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFalpha, IL-1beta, IL-6, IL-8, IL-10, transforming growth factor-beta, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.
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PMID:Adipokines: inflammation and the pleiotropic role of white adipose tissue. 1546 38

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children.
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PMID:Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants. 1554 94

Adipose tissue is a major source of inflammatory and thrombotic cytokines. This study investigated the relationship of abdominal subcutaneous adipose tissue cytokine gene expression to body composition, fat distribution, and metabolic risk during obesity. We determined body composition, abdominal fat distribution, plasma lipids, and abdominal subcutaneous fat gene expression of leptin, TNF-alpha, IL-6, PAI-1, and adiponectin in 20 obese, middle-aged women (BMI, 32.7 +/- 0.8 kg/m2; age, 57 +/- 1 yr). A subset of these women without diabetes (n = 15) also underwent an OGTT. In all women, visceral fat volume was negatively related to leptin (r = -0.46, P < 0.05) and tended to be negatively related to adiponectin (r = -0.38, P = 0.09) gene expression. Among the nondiabetic women, fasting insulin (r = 0.69, P < 0.01), 2-h insulin (r = 0.56, P < 0.05), and HOMA index (r = 0.59, P < 0.05) correlated positively with TNF-alpha gene expression; fasting insulin (r = 0.54, P < 0.05) was positively related to, and 2-h insulin (r = 0.49, P = 0.06) tended to be positively related to, IL-6 gene expression; and glucose area (r = -0.56, P < 0.05) was negatively related to, and insulin area (r = -0.49, P = 0.06) tended to be negatively related to, adiponectin gene expression. Also, adiponectin gene expression was significantly lower in women with vs. without the metabolic syndrome (adiponectin-beta-actin ratio, 2.26 +/- 0.46 vs. 3.31 +/- 0.33, P < 0.05). We conclude that abdominal subcutaneous adipose tissue expression of inflammatory cytokines is a potential mechanism linking obesity with its metabolic comorbidities.
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PMID:Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors. 1556 50

Diabetes mellitus is increasing worldwide, resulting from the interaction of obesity, inflammation, and hyperglycemia. Activated immunity and cytokine production lead to insulin resistance and other components of the metabolic syndrome, establishing the link between diabetes and atherosclerosis. Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial inflammation and vasa vasorum neovascularization in experimental models of diabetic atherosclerosis. Recent studies have documented increased inflammation, neovascularization, and intraplaque hemorrhage in human diabetic atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque rupture, leading to coronary thrombosis. Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor glycemic control. Circulating tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among inflammation, plaque rupture, and blood thrombogenicity. High-density lipoproteins, responsible for free cholesterol removal, are reduced in patients with insulin resistance and diabetes. High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant Apolipoprotein A-I Milano/phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of atherosclerosis. Three subfamilies, including PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque inflammation, expression of adhesion molecules and cytokines, and regulation of matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes atherosclerosis.
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PMID:New aspects in the pathogenesis of diabetic atherothrombosis. 1560 89

In 1980, the term non-alcoholic steatohepatitis was coined to describe a new syndrome occurring in patients who usually were obese (often diabetic) females who had a liver biopsy picture consistent with alcoholic hepatitis, but who denied alcohol use. The causes of this syndrome were unknown, and there was no defined therapy. More than two decades later, this clinical syndrome is only somewhat better understood, and still there is no Food and Drug Administration-approved or even generally accepted drug therapy. Patients with primary non-alcoholic steatohepatitis typically have the insulin resistance syndrome (synonymous with the metabolic syndrome, syndrome X, and so forth), which is characterized by obesity, diabetes, hyperlipidemia, hypertension, and, in some instances, other metabolic abnormalities such as polycystic ovary disease. Secondary non-alcoholic steatohepatitis may be caused by drugs such as tamoxifen, certain industrial toxins, rapid weight loss, and so forth. The cause of non-alcoholic steatohepatitis remains elusive, but most investigators agree that a baseline of steatosis requires a second hit capable of inducing inflammation, fibrosis, or necrosis for non-alcoholic steatohepatitis to develop. Our research group has focused its efforts on the interactions of nutritional abnormalities, cytokines, oxidative stress with lipid peroxidation, and mitochondrial dysfunction in the induction of steatohepatitis, both alcoholic and non-alcoholic in origin. Research findings from other laboratories also support the role of increased cytokine activity, oxidative stress, and mitochondrial dysfunction in the pathogenesis of non-alcoholic steatohepatitis. The objectives of this article are to review the (1) definition and clinical features of non-alcoholic steatohepatitis, (2) potential mechanisms of non-alcoholic steatohepatitis, and (3) potential therapeutic interventions in non-alcoholic steatohepatitis.
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PMID:Mechanisms of non-alcoholic steatohepatitis. 1567 Jun 68


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