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

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit phenotypic characteristics associated with noninsulin-dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese-diabetes phenotype was similar to that observed in the agouti and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemically expressed the gas6-binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF-alpha production indirectly resulting in the NIDDM phenotype.
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PMID:Noninsulin-dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor. 1052 29

Several types of abnormal lipoprotein particles are observed in patients with insulin resistance: elevated VLDL-triglycerides, remnant lipoprotein, small dense LDL, reduced HDL-cholesterol. These patterns are caused by environmental and genetic factors that alter the lipoprotein metabolism. These lipoprotein abnormalities cause insulin resistance through several factors which decrease LPL and PPAR gamma, on the other hand increase ACS and MTP. It is considered that increased plasma level of FFA will closely associated with these factors and their regulations. Secretion of TNF-alpha from adipocytes increases in obesity and closely relates to the pathogenesis of insulin resistance. But the genetic mechanisms are not still clear. More studies about genetic factors which affect to lipoprotein metabolism will be needed and should be considered about the role on insulin resistance.
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PMID:[Molecular mechanism of insulin resistance in hyperlipidemia]. 1063 92

Uncoupling protein 2 (UCP2) has been proposed to play a prominent role in the regulation of energy balance. UCP2 mRNA expression is upregulated in white adipose tissue (WAT) and liver, but is not altered in skeletal muscle in genetically obese ob/ob mice. The mechanisms involved in the upregulation of UCP2 in obesity have not been investigated. We have now examined the potential role of leptin, hyperphagia, increased tissue lipid content, and overexpression of tumor necrosis factor (TNF)-alpha in the upregulation of UCP2 mRNA expression in the liver and WAT in ob/ob mice. Treatment of ob/ob mice with leptin for 3 days significantly reduced their food intake but had no effect on the upregulation of UCP2 mRNA levels in the liver or WAT. To investigate the effect of feeding and higher tissue lipid content on the upregulation of UCP2 in liver and WAT, we compared UCP2 mRNA levels in ad-libitum fed and 72-h fasted control and ob/ob mice. In controls, fasting had no effect on UCP2 mRNA levels in liver, but increased UCP2 mRNA in WAT suggesting that the effects of fasting on UCP2 mRNA levels are tissue-specific. In ob/ob mice, fasting did not lower UCP2 mRNA levels in liver or WAT suggesting that the upregulation of UCP2 in ob/ob mice is not merely a direct consequence of increased food intake. 72-h fasting lowered hepatic total lipid content by 34% and 36% in control and ob/ob mice, respectively, without any corresponding decrease in hepatic UCP2 mRNA levels, suggesting that the enhanced UCP2 expression in the liver of ob/ob mice is not secondary to lipid accumulation in their livers. Although TNF-alpha has been shown to acutely increase UCP2 mRNA levels in liver and WAT, and is overexpressed in adipose tissue in obesity, deletion of the genes for both TNF receptors in ob/ob mice produces a further increase in UCP2 mRNA expression in liver and adipose tissue indicating a paradoxical inhibitory role. Taken together, these results suggest that the upregulation of UCP2 mRNA levels in the liver and WAT of ob/ob mice is not due to the lack of leptin, hyperphagia, increased tissue lipid content, or over-expression of TNF-alpha.
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PMID:Upregulation of uncoupling protein 2 mRNA in genetic obesity: lack of an essential role for leptin, hyperphagia, increased tissue lipid content, and TNF-alpha. 1068 29

The importance of free fatty acids (FFA) and adipocytokines released from adipocytes in the development of insulin resistance is discussed in this review article. FFA may cause insulin resistance through so-called Rundle cycle and may also inhibit glucose uptake by skeletal muscles. Adipocytokines, bioactive substances secreted from adipose tissue may have important roles in occurrence of insulin resistance. For example, TNF-alpha from adipocytes reduces tyrosine kinase activity of the insulin receptor in obesity. A novel collagen-like protein, adiponectin inhibits TNF-alpha induced cell phenomena and its reduction at obesity may be one of molecular mechanism of insulin resistance.
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PMID:[Adipocyte function and insulin resistance]. 1070 55

Multiple risk factor syndrome (MRFS) is a clustering of cardiovascular risk factors, which describes the epidemiological association of glucose intolerance, central obesity, hypertension, increased triglyceride level and decreased HDL-cholesterol, leading to the atherosclerosis. Insulin resistance is diagnosed clinically by fasting hyperinsulinemia, steady state plasma glucose (SSPG) method, insulin tolerance test and glucose clamp study. Visceral fat accumulation is supposed to play a central role in pathogenesis of MRFS and induces risk factors for cardiovascular disease through the increased TNF-alpha expression in adipose tissue and serum FFA level, which cause insulin resistance state. These risk factors should be prevented at early stage by the intervention in obesity, especially visceral fat accumulation.
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PMID:[Diagnostic criteria of insulin resistance and multiple risk factor syndrome]. 1070 66

Obesity is considered as the most important risk factor for type 2 diabetes. We will briefly discuss why does obesity predispose to diabetes, when does diabetes occur in obese subjects and who among obese individuals is particularly prone to develop diabetes. Obesity, especially intraabdominal adiposity, is associated with increased FFA plasma concentrations which exert a major negative effect on insulin sensitivity at both muscular and hepatic sites. Various metabolic, haemodynamic and hormonal theories have been proposed to explain insulin resistance in obese subjects. A specific role of TNF-alpha has been recently suggested. However, besides insulin resistance, defective insulin secretion is a prerequisie for the development of overt type 2 diabetes. Both lipotoxicity and glucotoxicity may initiate and perpetuate a vicious circle responsible for the metabolic deterioration. Diabetes occurs as a late phenomenon in obesity and is preceded by years of impaired glucose tolerance. The progression to diabetes is heralded by an inability of the B cell to maintain its previously high rate of insulin secretion in response to glucose in face of insulin resistance. This propensity to develop type 2 diabetes may be genetically determined and/or triggered by environmental factors. The evolution from obesity to diabetes represents a continuum that progresses through different phases in which defects in both insulin action and insulin secretion play a critical interaction and must be looked at in concert.
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PMID:From obesity to diabetes: why, when and who? 1078 2

By comparing the hepatic responses to tumor necrosis factor (TNF)-alpha that occur during situations that promote liver injury (such as obesity or chronic exposure to ethanol) with those that occur after stimuli (such as partial hepatectomy) that lead to liver regeneration, it is apparent that hepatocytes are usually able to constrain noxious responses to TNF-alpha, such as the release of reactive oxygen from mitochondria. It appears that by promptly upregulating survival genes that regulate mitochondrial membrane permeability, hepatocytes are usually able to constrain noxious responses, including the release of mitochondrial-generated reactive oxygen species, that follow exposure to potentially toxic cytokines, such as TNF-alpha. Indeed, transient TNF-alpha-mediated increases in ROS may even be exploited by hepatocytes to evoke a subsequent proliferative response. Thus, the healthy liver has well-developed defense mechanisms that permit hepatocytes to adapt to cytokine-initiated stress, protecting them from cytokine-mediated lethality. Nevertheless, these same cytokines may cause liver injury when hepatocytes have been pre-exposed to toxins (e.g. ethanol) that interfere with their usual protective responses. Furthermore, while transient adaptations to cytokine-initiated stress permit hepatocytes to survive and proliferate, persistence of these anti-apoptotic, adaptative responses (as occurs, for example, in fatty livers) may inadvertently enhance hepatocyte vulnerability to necrosis when the liver is confronted by secondary insults that promote mitochondrial membrane depolarization.
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PMID:Cytokine regulation of liver injury and repair. 1080 15

Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are characteristic for obesity and are associated with increased risk of thromboembolic complications. PAI-1 recently was reported to be expressed and secreted by human adipocytes, but little is known about regulation of PAI-1 in human adipose tissue. Therefore, we examined the effects of selected cytokines present in adipose tissue on expression and secretion of PAI-1 in in vitro, differentiated subcutaneous human adipocytes in primary culture. Transforming growth factor-beta1 (TGF-beta1) increased PAI-1 secretion in a dose- and time-dependent manner. PAI-1 protein increased by 3.2-fold and PAI-1 mRNA by 1.9-fold after a 6-hour exposure to 400 pmol/L TGF-beta1. This effect is probably mediated by TGF-beta1 type 2 and 3 receptors, which were found to be expressed in cultured human adipocytes. Moreover, TNF-alpha and interkeukin-1beta (IL-1beta) also exerted a stimulatory effect on PAI-1 release and increased PAI-1 mRNA levels. As assessed by a semiquantitative reverse transcription-polymerase chain reaction technique, TGF-beta1 mRNA is expressed by differentiation of human preadipocytes and is moderately upregulated by TNF-alpha and IL-1beta. In conclusion, our results clearly indicate that TGF-beta1 is a potent inducer of PAI-1 production in subcutaneous human adipocytes. In addition, data suggest that TNF-alpha and IL-1beta also have stimulatory effects on PAI-1 protein secretion and may contribute to the elevated PAI-1 levels observed in obesity.
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PMID:Role of cytokines in the regulation of plasminogen activator inhibitor-1 expression and secretion in newly differentiated subcutaneous human adipocytes. 1084 89

Obesity represents a serious risk factor for the development of cardiovascular diseases, including hypertension. Segregation studies suggest that obesity and obesity-associated hypertension may share some genetic determinants. The results of the present candidate gene investigation suggest that in hypertensive pedigrees of French-Canadian origin, one such determinant is the tumor necrosis factor (TNF)-alpha gene locus. Gender-pooled quantitative sib-pair analysis demonstrated a significant effect of the gene locus on 3 global and 7 regional measures of obesity (P=0.05 to 0.0004). Gender-separate quantitative sib-pair analyses showed that the impact of the locus on obesity is most significant in the abdominal region in men and in the thigh region in women. Furthermore, the haplotype relative-risk test demonstrated a significant association between the TNF-alpha gene locus and both obesity (P=0.006) and obesity-associated hypertension (P=0.02). These effects were most significant in individuals with nonmorbid obesity. In conclusion, the results of linkage and association analyses suggest that in hypertensive pedigrees of French-Canadian origin, the TNF-alpha gene locus contributes to the determination of obesity and obesity-associated hypertension. In addition, the data indicate that gender modifies the effect of the locus on the regional distribution of body fat.
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PMID:Role of tumor necrosis factor-alpha gene locus in obesity and obesity-associated hypertension in French Canadians. 1090 6

Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. There was no significant correlation (r = 0.11) between secretion of adipose plasminogen activator inhibitor 1 and glucose transport. Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women.
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PMID:Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. 1090 74


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