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

Aberrant TNF alpha expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNF alpha-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNF alpha, we demonstrate that specific expression of the transmembrane TNF alpha (mTNF alpha) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNF alpha in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.
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PMID:Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. 1189 9

We have recently identified the winged helix/forkhead gene Foxc2 as a key regulator of adipocyte metabolism that counteracts obesity and diet-induced insulin resistance. This study was performed to elucidate the hormonal regulation of Foxc2 in adipocytes. We find that TNF alpha and insulin induce Foxc2 mRNA in differentiated 3T3-L1 cells with the kinetics of an immediate early response (1-2 h with 100 ng/ml insulin or 5 ng/ml TNF alpha). This induction is, in both cases, attenuated by the PI3K inhibitor wortmannin as well as the MAPK kinase inhibitor PD98059. Furthermore, we show that stimulation of 3T3-L1 adipocytes with phorbol-12-myristate-13-acetate or 8-(4-chlorophenyl)thio-cAMP induces the expression of Foxc2. Interestingly, we find that the basal level of Foxc2 mRNA is down-regulated whereas hormonal responsiveness increases during differentiation of 3T3-L1 from preadipocytes to adipocytes. At the protein level, immunoblots with Foxc2 antibody demonstrated an induction of Foxc2 by insulin and TNF alpha in nuclear extracts of 3T3-L1 adipocytes. EMSA of nuclear proteins from phorbol-12-myristate-13-acetate- and TNF alpha-treated 3T3-L1 adipocytes using a forkhead consensus oligonucleotide revealed specific binding of a Foxc2/DNA complex. In conclusion, our data suggest that insulin and TNF alpha regulate the expression of Foxc2 via a PI3K- and ERK 1/2-dependent pathway in 3T3-L1 adipocytes. Also, signaling pathways downstream of PKA and PKC induce the expression of Foxc2 mRNA.
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PMID:Insulin and TNF alpha induce expression of the forkhead transcription factor gene Foxc2 in 3T3-L1 adipocytes via PI3K and ERK 1/2-dependent pathways. 1192 82

Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.
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PMID:The biology of white adipocyte proliferation. 1211 95

Inflammatory cytokines such as TNF alpha may play a role in the pathogenesis of common metabolic disorders, including hyperandrogenism and the polycystic ovary syndrome (PCOS). The TNF receptor 2 mediates most of the metabolic effects of TNF alpha. In the present study, we have evaluated serum soluble TNF receptor 2 levels, and several common polymorphisms in the TNF receptor 2 gene (TNFRSF1B), in women presenting with PCOS or hyperandrogenic disorders. Initial studies included 103 hyperandrogenic patients (42 presenting with PCOS) and 36 controls from Spain. The 196R alleles of the M196R (676 T-->G) variant in exon 6 of TNFRSF1B, which is in linkage disequilibrium with a CA-repeat microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more frequent in hyperandrogenic patients than in controls (P = 0.056), reaching statistical significance when the analysis was restricted to include only PCOS patients (P < 0.03). Extended analysis including another 11 hyperandrogenic patients from Spain and 64 patients and 29 controls from Italy confirmed the association between 196R alleles of the M196R variant and hyperandrogenic disorders (P < 0.05), which was maintained when restricting the analysis to PCOS patients (P < 0.02). On the contrary, the 3'-untranslated region (exon 10) variants 1663 G-->A, 1668 T-->G, and 1690 T-->C were not associated with hyperandrogenism. The soluble TNF receptor 2 levels were not different between patients and controls but were increased in obese subjects, compared with lean individuals, and were affected by the interaction between the 1663 G-->A and 1668 T-->G variants in the 3'-untranslated region of TNFRSF1B. The TNFRSF1B genotype did not influence any clinical or biochemical variable related to hyperandrogenism or insulin sensitivity and was not associated with obesity, both in hyperandrogenic patients and healthy controls considered separately. In conclusion, the M196R (676 T-->G) variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and PCOS, further suggesting a role for inflammatory cytokines in the pathogenesis of these disorders.
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PMID:Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. 1216 45

Obesity and type 2 diabetes are associated strongly with NAFLD. It is not clear if one of these conditions causes the others, or if all are consequences of another process. Although NAFLD is known to occur in overly lean individuals, which indicates that excessive adiposity is not required for the development of NAFLD, the severities of insulin resistance and NAFLD tend to parallel each other, and the greatest prevalence of type 2 diabetes occurs in patients with NAFLD and cirrhosis. This observation suggests that insulin resistance and NAFLD may be related pathogenically. Experiments in mice demonstrate that insulin resistance and NAFLD result from a chronic inflammatory state that is characterized by increased levels of TNF alpha. The mechanisms that drive this chronic inflammation are unknown but might involve the oxidative stress that develops during fatty acid metabolism or when products from intestinal bacteria escape into the mesenteric blood to trigger a sustained hepatic inflammatory cytokine response in genetically susceptible individuals, promoting a positive feedback loop that reinforces insulin resistance and inflammation. This hypothesis is supported by some animal and human studies; however, more research is needed to evaluate this theory. Additional studies also are required to determine the benefits of treatments that interrupt this pathogenic cascade at various points. Preliminary work in animal and human studies suggests that diverse strategies that inhibit production of TNF alpha and improve insulin resistance also ameliorate NAFLD.
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PMID:The liver in obesity and type 2 diabetes mellitus. 1251 96

Glucocorticoids are regulated at the prereceptor level by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11 beta-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11 beta-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11 beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11 beta-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9)M (65 +/- 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9) M (65 +/- 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11 beta-HSD-1 mRNA expression. TNF alpha up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (140 +/- 20%; P < 0.001); the same cytokine increased 11 beta-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 +/- 14% of control (P < 0.01). IL-1 beta also up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (160 +/- 33%; P < 0.001) and caused an increase in glycerol levels (159 +/- 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol up-regulated 11 beta-HSD-1 activity maximally at 10(-7) M (162 +/- 46%; P < 0.02), and clonidine down-regulated it at 10(-7) M (82 +/- 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11 beta-HSD-1 might include down-regulation of 11 beta-HSD-1 activity by CRH, ACTH, and alpha 2 sympathetic stimulation, and up-regulation of the enzyme by beta 2 sympathetic stimulation and by the cytokines TNFalpha and IL-1 beta.
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PMID:Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. 1251 81

Tumour necrosis factor alpha (TNF-alpha), acting as a modulator of gene expression in adipocytes, has been linked to the development of insulin resistance and obesity. The aim of this study was to investigate whether the A/G variation at position -308 in the TNF-alpha promoter influences the body weight, insulin resistance, and postprandial lipaemia in Polish Caucasians. One hundred twenty one subjects, 38 men and 83 women, representing 40 obese families, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). TNF-1 (GG) and TNF-2 (GA and AA) allele carriers were compared with respect to body mass index, fat/lean body mass composition, waist-to-hip ratio, as well as fasting lipids, glucose, leptin, and insulin fasting, and during the oral glucose tolerance test (4 points within 2 hours) and oral lipid tolerance test (OLTT; 5 points within 8 hours). The insulin sensitivity indices HOMA-IR (homeostasis model assessment of insulin resistance), ISI-COMP (whole body insulin sensitivity index), ISI-HOMA (hepatic insulin sensitivity), and DELTA (early secretory response to an oral glucose load) were calculated. We detected 64 GG, 56 GA, and 1 AA genotypes. Significant increases of insulin resistance parameters in obese female TNF-2 allele carriers were observed (significantly increased HOMA-IR and decreased ISI-HOMA, ISI-composite). The male TNF-2 carriers were characterised by significantly increased levels of triglyceride and free fatty acids during OLTT as well as fasting glucose. The A/G variation at position -308 in the promoter region of the TNF-alpha gene could be an important genetic factor predisposing to insulin resistance in obese women and increased levels of glucose, triglyceride, and free fatty acids in men.
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PMID:The TNF-alpha gene NcoI polymorphism at position -308 of the promoter influences insulin resistance, and increases serum triglycerides after postprandial lipaemia in familiar obesity. 1274 94

Obstructive sleep apnoea (OSA) is a very prevalent disorder particularly amongst middle-aged, obese men, although its existence in women as well as in lean individuals is increasingly recognized. Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a 'local abnormality' of the respiratory track rather than as a 'systemic illness'. In 1997, we first reported that the pro-inflammatory cytokines interleukin (IL)-6 and tumour necrosis factor-alpha (TNF alpha) were elevated in patients with disorders of excessive daytime sleepiness (EDS) and proposed that these cytokines were mediators of daytime sleepiness. Also, we reported a positive correlation between IL-6 or TNF alpha plasma levels and the body mass index (BMI). In subsequent studies, we showed that IL-6, TNF alpha, leptin and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat, was the primary parameter linked with sleep apnoea. The association of OSA with insulin resistance and diabetes type 2 has been confirmed since then in several epidemiological and clinical studies. Furthermore, our findings that women with polycystic ovary syndrome (PCOS, a condition associated with hyperandrogenism and insulin resistance) were much more likely than controls to have sleep disordered breathing (SDB) and daytime sleepiness support the pathogenetic role of insulin resistance in OSA. Other findings that support the view that sleep apnoea and sleepiness may be manifestations of a serious metabolic disorder, namely the Metabolic or Visceral Obesity Syndrome, include: obesity without sleep apnoea is associated with daytime sleepiness; PCOS and diabetes type 2 are independently associated with EDS after controlling for SDB, obesity and age; and increased prevalence of sleep apnoea in postmenopausal women, with hormonal replacement therapy associated with a significantly reduced risk for OSA. In conclusion, accumulating evidence provides support to our model of the bi-directional, feedforward, pernicious association between sleep apnoea, sleepiness, inflammation and insulin resistance, all promoting atherosclerosis and cardiovascular disease.
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PMID:Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. 1282 41

The adipose tissue plays a fundamental role in maintaining the energy balance in mammals. During periods of high energy intake, the adipocytes store energy in the form of fat (triglycerides), which can be mobilized as free fatty acids during energy deprivation. Adipose tissue can no longer be considered only as a passive tissue that simply stores energy. Some recent discoveries have made it evident that this is a very active endocrine tissue that secretes important molecules related to different processes such as the immune response (TNF alpha) the regulation of food intake and expenditure of energy (leptin, Acrp30/adipoQ) and the vascular function (angiotensin and plasminogen activator inhibitor type 1). Alterations in the growth, development and function of the adipose tissue might therefore be involved in the development of different pathologies such as obesity, insulin resistance and type 2 diabetes, hypertension and atherosclerosis. A deeper understanding of the adipose tissue (morphology, development-adipogenesis, role in the metabolism and in the regulation of body weight, endocrine functions.) is needed for an adequate study of the underlying aspects in the development of obesity.
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PMID:[Adipose tissue: a storage and secretory organ]. 1286 Dec 68

The insulin resistance syndrome (IRS) with obesity is large-word wide-spread and represents a strong risk factor for vascular disease. Atherothrombotic complications in IRS are partly attributed to a dysregulation of hemostasis inducing a prothrombotic state which includes endothelial activation, hyperactivity of platelets, hypercoagulability and hypofibrinolysis. This latter, due to elevated PAI-1 levels, is a core feature of the IRS. Most of the prothrombotic modifications can be reversed by loosing weight. Low grade inflammation with prolonged cytokines mediated acute phase reaction is actually considered as strongly related to the IRS and is involved in the dysregulation of hemostasis. TNF pathway and TGFb play an important role in the regulation of PAI-1 synthesis in the adipose tissue and the liver with steatosis. Interestingly, modulation of PAI-1 expression in adipose tissue influences adipose tissue growth, increasing once more the spectrum of the non hemostatic functions of coagulation/fibrinolysis parameters.
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PMID:The insulin resistance syndrome: implications for thrombosis and cardiovascular disease. 1367 55


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