UMLS:C0028754 - FACTA Search

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

Previous studies have indicated that rodents are relatively resistant to diet-induced obesity and that this resistance may be mediated in part by the capacity for diet-induced thermogenesis in brown adipose tissue (BAT). To test this hypothesis, we fed UCP-DTA transgenic with toxigene-mediated ablation of BAT and their control littermates a "Western diet" [21% (wt/wt) fat] or normal mouse chow [6.5% (wt/wt) fat]. The diets were begun at weaning (19 days old). At the age of 12 weeks, transgenic mice receiving the Western diet were markedly obese. The increased body weight and total body lipid content were significantly greater in transgenic mice receiving the Western diet than were the additive individual effects of Western diet (in control mice) and decreased BAT (in chow-fed mice), suggesting a synergistic interaction between diminished BAT and diet. A synergistic effect of Western diet and BAT ablation was also observed for morbid metabolic complications, such as insulin resistance, hyperglycemia, and hyperlipidemia. These metabolic changes were accompanied by increased expression of tumor necrosis factor-alpha and decreased expression of GLUT4 and beta 3-adrenergic receptor messenger RNA levels in white adipose tissue of UCP-DTA transgenic mice receiving the Western diet compared to those in the other experimental groups. As previously described, transgenic mice with diminished brown fat are hyperphagic. Of note, the degree of hyperphagia in transgenics compared to controls was similar whether the animals were fed chow or a Western diet. Thus, the synergistic effect of Western diet on obesity in transgenic mice was not mediated by a further stimulation of food intake. Overall, this study demonstrates the existence of a synergistic interaction between decreased BAT and Western diet to cause marked obesity and its accompanying disorders, such as insulin resistance and hyperlipidemia, and gives further support for the view that an important function of BAT is protection from diet-induced obesity, diabetes, and insulin resistance.
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PMID:Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. 853 14

In summary, over-expression of GLUT4 selectively in fat causes increased flux of glucose into adipocytes and leads to increases in either the replication of immature pre-adipocytes or their differentiation into mature adipocytes resulting in an increase in fat cell number. This is the first model in which obesity is accounted for entirely by adipocyte hyperplasia and, therefore, is useful for studying the mechanisms involved in controlling fat cell number in vivo. GLUT4 over-expression in adipocytes of transgenic animals also increased whole- body insulin sensitivity. However, GLUT4 over-expression exclusively in adipocytes did not protect them from insulin resistance in vivo induced by high-fat feeding, in spite of the fact that insulin resistance was prevented at the level of the adipocyte. Interestingly, GLUT4 over-expression in fat protected the animals from developing further obesity when fed on a high-fat diet. It is possible that this failure to increase adiposity further is due to enhanced partitioning of glucose into fat, which may result in decreased glucose supply to muscle. This in turn may cause diversion of lipid to muscle to be oxidized as fatty acid. This diversion of lipid could result in protection against increased fat deposition in adipocytes. Further studies will be required in order to understand the molecular mechanisms by which GLUT4 over-expression in adipose tissues affects nutrient partitioning between muscle and adipose tissue and what the consequences of this are for whole-body fuel metabolism.
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PMID:Over-expression of GLUT4 selectively in adipose tissue in transgenic mice: implications for nutrient partitioning. 883 91

To investigate whether inheritance or obesity plays a more important role in the development of non-insulin-dependent diabetes mellitus (NIDDM), female Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, which possess the diabetogenic gene, ODB-1, and Long-Evans-Tokushima-Otsuka (LETO) rats, which have no ODB-1, were compared. Neither strain becomes obese and diabetic when bred ordinarily. Female OLETF rats and male and female LETO rats were assigned to two groups of 20 rats each. Obesity was induced in one group by feeding a high-energy "cafeteria" diet (group D), and the other group was given standard chow (group C). Twenty male OLETF rats were used as NIDDM positive controls. At 25 weeks of age, the mean body weight of group D male LETO and female OLETF rats increased at a rate similar to that of male OLETF rats; female LETO rats did not show increased body weight. The incidence of diabetes mellitus in obese female OLETF rats in group D and positive control male OLETF rats was the same (80%). Only 30% of obese male LETO rats in group D developed diabetes mellitus. The insulin response to intravenous glucose in group D female OLETF rats was the highest for all groups but not sufficient to decrease blood glucose levels. In female OLETF rats, glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp test in group D was decreased to 50% of the group C value and tissue glucose uptake as determined by 3H-glucose infusion was significantly decreased in muscle. In male LETO rats, group D GIR was mildly decreased (80% of group C value) compared with the GIR of female OLETF rats. For obese group D female OLETF rats, abdominal fat increased more with obesity than in their male LETO counterparts. GIR was inversely correlated with the weight of abdominal fat when the data of all groups of animals were combined. The expression of GLUT4 mRNA and its protein level in adipose and muscle tissues and tumor necrosis factor alpha (TNF-alpha) protein in adipose tissue were not significantly different between group D and group C of both strains. In conclusion, the incidence of diabetes in female OLETF rats that possess the diabetogenic gene was significantly greater than in the LETO strains that do not possess the gene, in the presence of excess adiposity.
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PMID:Obesity is necessary but not sufficient for the development of diabetes mellitus. 884 87

The effect of insulin to acutely stimulate glucose uptake into muscle and adipose tissue is essential for normal glucose homeostasis. The GLUT4 glucose transporter is a major mediator of this action, and insulin recruits GLUT4 from an intracellular pool to the plasma membrane. An important pathologic feature of obesity, NIDDM, and to a lesser extent IDDM is resistance to insulin-stimulated glucose uptake. Investigations of the mechanisms have revealed tissue-specific regulation of GLUT4 with decreased gene expression in adipose cells but not in skeletal muscle. This has led to the hypothesis that alterations in the trafficking of the GLUT4 vesicle or in the exposure or activation of the GLUT4 transporter may cause insulin resistance in skeletal muscle in obesity and diabetes. Exercise training increases GLUT4 expression in muscle in association with enhanced glucose tolerance in vivo. Transgenic mice have been created to investigate other approaches to improve insulin action on glucose transport. Overexpression of GLUT4 in adipocytes of transgenic mice increases the proportion of GLUT4 on the plasma membrane and enhances insulin sensitivity in vivo. Altering insulin signaling by overexpressing p21ras in adipocytes of transgenic mice results in increased GLUT4 on the plasma membrane in the absence of insulin and increases insulin sensitivity in vitro and in vivo. Thus, glucose transport is a pivotal step in whole-body insulin action. Strategies to increase the number of GLUT4 transporters that are functionally inserted in the plasma membrane in muscle and adipocytes may lead to new therapies to treat or prevent NIDDM.
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PMID:Lilly lecture 1995. Glucose transport: pivotal step in insulin action. 886 74

Adipocytes produce a variety of molecules that are capable of functioning in both a paracrine and autocrine fashion. Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. This finding has led to the idea that TNF produced by adipocytes functions as a local "adipostat" to limit fat accumulation. Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. These findings raise the possibility that pharmacological inhibition of TNF may provide a novel therapeutic target to treat patients with NIDDM.
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PMID:Inhibition of insulin receptor signaling by TNF: potential role in obesity and non-insulin-dependent diabetes mellitus. 889 94

Polymorphic variation of genes encoding the glucose transporters glycoproteins (GLUT) may contribute to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes. In this study we evaluated the allele and genotype frequencies of GLUT1 and GLUT4 restriction fragment length polymorphism (RFLP), revealed by digestion with XbaI for GLUT1 and KpnI for GLUT4, in Caucasian, Chinese, Japanese, Asian Indian and American black populations. No differences of the KpnI GLUT 4 RFLP were found between control and diabetic subjects in any ethnic group or when all data are combined. In contrast, positive results were found for the XbaI RFLP: (1) most ethnic groups showed an association of allele 1 with type 2 diabetes, and this association was maintained when all groups were analysed together; (2) after stratifying for sex and obesity, this association was significant only for overweight/obese women. This joint analysis suggests that GLUT1 polymorphism may contribute to susceptibility to type 2 diabetes in some populations, and especially in overweight/obese women.
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PMID:Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 (non-insulin-dependent) diabetes mellitus in different populations. 890 24

A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. Reports on the mechanism of TNF-alpha action have been somewhat contradictory. GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. Nevertheless, the remaining proteins appear to be biochemically indistinguishable from those in untreated adipocytes. Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes.
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PMID:Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. 899 90

Members of the Rab 3 subfamily of low-molecular-mass GTP-binding proteins have been functionally implicated in regulated exocytosis. The aim of the present study was to examine the subcellular distribution of a member of this family, Rab 3D, in rat adipose cells, given the hypothesis that this protein might be involved in insulin-stimulated GLUT4 exocytosis. We show that Rab 3D immunoreactivity is associated predominantly with the high-density microsomal fraction, where the signal intensity is 3- and 7-fold greater than that in plasma membranes and low-density microsomes respectively. Rab 3D does not co-localize with GLUT4 on immuno-isolated intracellular vesicles and, unlike GLUT4, it is not redistributed in response to insulin. Thus, if Rab 3D plays a role in GLUT4 trafficking, it relies on mechanisms independent of relocation. We observed that Rab 3D is overexpressed in adipose cells of obese (fa/fa) Zucker rats, in a tissue- and isoform-specific manner. The pathophysiological significance of this defect remains elusive. This could form the molecular basis for altered adipose secretory function in obesity.
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PMID:Rab 3D in rat adipose cells and its overexpression in genetic obesity (Zucker fatty rat). 900 5

Insulin resistance is a manifestation of both diabetes mellitus and obesity. However, the mechanism is still not clearly identified. Herein, we describe a procedure that allows us to evaluate the development of insulin resistance in 3T3-L1 adipocytes. Under these conditions, we show that the concentration of insulin required for 50% desensitization of glucose transport activity is 100 pM; maximal desensitization could be achieved with 1 nM. This demonstrates for the first time that 3T3-L1 adipocytes develop insulin resistance in response to physiologically relevant concentrations of insulin. Glucose (or glucosamine), in addition to insulin, was required to establish desensitization. The expression of GLUT4 protein decreased by 50% with exposure to 10 nM insulin. The dose-dependent loss of GLUT4 was similar to the dose dependence for insulin-resistant transport activity. Translocation in the presence of acute insulin was apparent, but the extent of recruitment directly reflected the decrease in GLUT4 protein. GLUT4 mRNA also declined, but the ED50 was approximately 5 nM. Together, these data suggest that the loss of GLUT4 protein likely underlies the cause of desensitization. However, the loss of GLUT4 protein did not correlate with the loss in GLUT4 mRNA suggesting post-translational control of GLUT4 expression.
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PMID:Development of insulin resistance in 3T3-L1 adipocytes. 906 37

The male Otsuka Long-Evans Tokushima Fatty (OLETF) rat shows insulin resistance in skeletal muscle and visceral obesity. To obtain information on the mechanism of the insulin resistance in the diabetic rats, we examined the content of insulin-regulated glucose transporter (GLUT4) in skeletal muscles. The results indicate that the total content of the transporter is significantly decreased (P < 0.05) in muscles of the diabetic rats. Plasma membrane content of the GLUT4 protein in muscles of the diabetic rats was increased in the basal state as compared to control rats. Hyperinsulinemic clamps increased GLUT4 levels in the plasma membrane of control rats but failed to do so in the diabetic rats. The distribution of GLUT4 in OLETF rat is reminiscent of the characteristics of human non-insulin-dependent diabetes mellitus.
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PMID:Plasma membrane content of insulin-regulated glucose transporter in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty rat, a model of non-insulin-dependent diabetes mellitus. 917 78

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