Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF alpha) is a cytokine implicated in the development of septic shock, cachexia, and other pathological states. Recent studies indicated a direct role for adipose expression of TNF alpha in obesity-linked insulin resistance and diabetes. Pioglitazone, CP-86,325 (CP), AD-5075, CS-045, ciglitazone, and englitazone are members of a new class of insulin-sensitizing thiazolidinedione derivatives with in vivo antidiabetic activities. To test whether these agents antagonize the effect of TNF alpha, 3T3-L1 cells were induced to differentiate in the presence of TNF alpha with or without thiazolidinedione derivatives. Incubation of 3T3-L1 cells with TNF alpha alone completely inhibited adipocyte conversion and expression of fatty acid-binding protein messenger RNA (mRNA). However, coincubation of TNF alpha-treated cells with CP (1 microM), AD-5075 (1 microM), pioglitazone (10 microM), or CS-045 (10 microM) blocked these effects. Long term incubation of 3T3-L1 adipocytes with a low dose of TNF alpha (50 pM) significantly decreased the levels of the adipocyte/muscle-specific glucose transporter (GLUT4) and the CCAAT enhancer-binding protein mRNAs, but did not affect expression of the ubiquitously expressed glucose transporter (GLUT1) or lipoprotein lipase mRNAs. Incubation of 3T3-L1 adipocytes with TNF alpha also inhibited insulin-stimulated 2-deoxyglucose uptake as well as expression of GLUT4 protein. Furthermore, in 3T3-L1 adipocytes, incubation with TNF alpha attenuated the expression of fatty acid-binding protein mRNA in a time- and dose-dependent manner. These inhibitory effects were partially or completely blocked by coincubation of the cells with CP. These results implicate that the insulin-sensitizing agents may exert their antidiabetic activities by antagonizing the inhibitory effects of TNF alpha.
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PMID:Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. 789 57

We assessed the content of two isoforms of glucose transporter (GLUT 1 and GLUT 4) in insulin-sensitive tissues of hypothalamic obese mice treated with either aurothioglucose (AuTG) or monosodium glutamate (MSG). The animals were studied when obesity had reached a plateau, and they were clearly insulin resistant. We studied different membrane fractions from white adipose tissue (WAT), such as fat-free extract (FFE), plasma membrane (PM) and microsomal (M) fractions. GLUT 4 expressed per protein content displayed a decrease of 50% (p < 0.001) in all membrane fractions of AuTG- and MSG-treated mice. The PM GLUT 4 content, expressed per cell surface area, was reduced by 70% (p < 0.001) in obese mice, and the total FFE GLUT 4, expressed per total fat mass, was 5 times reduced in obese mice. Compared to control mice, obese mice showed a reduction (p < 0.01) of the GLUT 4 amount by 30% (AuTG) and by 40% (MSG) in total membrane fraction (TM) of skeletal and cardiac muscles. Similarly, a reduction of the GLUT 4 amount by 40% (AuTG) and by 45% (MSG) in FFE of brown adipose tissue was observed. The GLUT 1 content in FFE of WAT and TM of skeletal muscle showed no significant difference among the different animal groups. These results confirm a decreased expression of GLUT 4, but not of GLUT 1, in insulin-sensitive tissues, which may contribute to the impaired glucose utilization in these obese animals.
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PMID:Decreased glucose transporter (GLUT 4) content in insulin-sensitive tissues of obese aurothioglucose- and monosodium glutamate-treated mice. 822 98

To gain insight into the molecular pathogenesis of obesity and specifically the role of nutrient partitioning in the development of obesity, we overexpressed the insulin-responsive glucose transporter (GLUT4) in transgenic mice under the control of the fat-specific aP2 fatty acid-binding protein promoter/enhancer. Two lines of transgenic mice were generated, which overexpressed GLUT4 6-9-fold in white fat and 3-5-fold in brown fat with no overexpression in other tissues. In vivo glucose tolerance was enhanced in transgenic mice. In isolated epididymal, parametrial, and subcutaneous adipose cells from transgenic mice, basal glucose transport was 20-34-fold greater than in nontransgenic littermates. Insulin-stimulated glucose transport was 2-4-fold greater in cells from transgenic mice. Total body lipid was increased 2-3-fold in transgenic mice overexpressing GLUT4 in fat. Surprisingly, fat cell size was unaltered and fat cell number was increased > 2-fold. This is the first animal model in which increased fat mass results solely from adipocyte hyperplasia and it will be a valuable model for understanding the mechanisms responsible for fat cell replication and/or differentiation in vivo.
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PMID:Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. 822 28

Mechanisms causing cellular insulin resistance in gestational diabetes mellitus are not known. We, therefore, studied isolated omental adipocytes obtained during elective cesarean sections in nondiabetic (control) and GDM gravidas. Cellular insulin resistance was attributed to impaired stimulation of glucose transport; compared with control subjects, basal and maximally insulin-stimulated transport rates (per surface area) were reduced 38 and 60% in GDM patients, respectively. To determine underlying mechanisms, we assessed the number, subcellular distribution, and translocation of GLUT4, the predominant insulin-responsive glucose transporter isoform. The cellular content of GLUT4 was decreased by 44% in GDM patients as assessed by immunoblot analysis of total postnuclear membranes. However, GDM patients segregated into two subgroups; half expected profound (76%) cellular depletion of GLUT4 and half had GLUT4 levels in the normal range. Cellular GLUT4 was negatively correlated with adipocyte size in the control subjects and GDM patients with normal GLUT4 (r = 0.60), but fell way below this continuum in GDM patients with low GLUT4, indicating that heterogeneity was not caused by differences in obesity. All GDM. distribution. In basal cells, increased amounts of GLUT4 were detected in membranes fractionating with (such that the plasma membrane GLUT4 level in GDM (such that the plasma membrane GLUT4 level in GDM patients was equal to that observed in insulin-stimulated cells from control subjects). Furthermore, insulin stimulation induced translocation of GLUT4 from low-density microsomes to plasma membranes in control subjects but did not alter subcellular distribution in GDM patients. In other experiments, cellular content of GLUT1 was normal in GDM patients, and GLUT1 did not undergo insulin-mediated recruitment to plasma membranes in either control subjects or GDM patients. A faint signal was detected for GLUT3 only in low-density microsomes and only with one of two different antibodies. In GDM, we conclude that insulin resistance in adipocytes involves impaired stimulation of glucose transport and arises from a heterogeneity of defects intrinsic to the glucose transport effector system. GLUT4 content in adipocytes is profoundly depleted in approximately 50% of GDM patients, whereas all patients are found to exhibit a novel abnormality in GLUT4 subcellular distribution. This latter defect is characterized by accumulation of GLUT4 in membranes cofractionating with plasma membranes and high-density microsomes in basal cells and absence of translocation in response to insulin. The data suggest that abnormalities in cellular traffic or targeting relegate GLUT4 to a membrane compartment from which insulin cannot recruit transporters to the cell surface and have important implications regarding skeletal muscle insulin resistance in GDM and NIDDM.
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PMID:Multiple defects in the adipocyte glucose transport system cause cellular insulin resistance in gestational diabetes. Heterogeneity in the number and a novel abnormality in subcellular localization of GLUT4 glucose transporters. 824 23

A metabolic hypothesis is presented for insulin resistance in obesity, in the presence or absence of Type 2 (non-insulin-dependent) diabetes mellitus. It is based on physiological mechanisms including a series of negative feed-back mechanisms, with the inhibition of the function of the glycogen cycle in skeletal muscle as a consequence of decreased glucose utilization resulting from increased lipid oxidation in the obese. It considers the inhibition of glycogen synthase activity together with inhibition of glucose storage and impaired glucose tolerance. The prolonged duration of increased lipid oxidation, considered as the initial cause, may lead to Type 2 diabetes. This hypothesis is compatible with others based on the inhibition of insulin receptor kinase and of glucose transporter activities.
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PMID:Metabolic origin of insulin resistance in obesity with and without type 2 (non-insulin-dependent) diabetes mellitus. 830 48

The obese diabetic SHR/N-cp rat is a newly developed strain that inherits obesity as an autosomal recessive trait. These rats display early-onset hyperinsulinemia and hyperglycemia, which are hallmarks of type II diabetes. This study was undertaken to determine the expression and the subcellular distribution of the GLUT1 and GLUT4 glucose transporters in skeletal muscle of obese diabetic SHR rats. D-glucose-protectable cytochalasin-B binding to subcellular membrane fractions of hindlimb muscles was used to determine glucose transporter number. GLUT1 and GLUT4 glucose transporter isotypes were detected using antibodies to the COOH-terminal region of the GLUT1 and GLUT4 proteins. Glucose transporter number was significantly lower (-40%) in crude unfractionated membranes of obese diabetic SHR than of lean SHR muscles. When crude membranes were fractionated to separate plasma membranes and the intracellular membranes containing glucose transporters, the number of cytochalasin-B binding sites was found to be markedly lower (-50%) in intracellular membranes and slightly but not significantly reduced (-20%) in plasma membranes of muscle from obese diabetic SHR compared with lean SHR rats. Western blot analysis revealed that a lower GLUT4 protein abundance (-40%) accounts for the reduced glucose transporter number in intracellular membranes of obese diabetic SHR compared with lean SHR muscles. GLUT4 protein content was also reduced by 50% in plasma membranes from obese SHR muscles relative to lean rat muscles.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential regulation of GLUT1 and GLUT4 glucose transporters in skeletal muscle of a new model of type II diabetes. The obese SHR/N-cp rat. 832 52

In this study we determined whether alterations in the expression of GLUT4, the major insulin-regulatable glucose transporter, in skeletal muscle could explain the insulin-resistant glucose uptake characteristic of both dietary-induced and genetic obesity. GLUT1 expression was measured for comparison. To assess glucose transporter protein levels in dietary-induced obesity, postnuclear membranes were prepared from hindlimb muscle of Sprague-Dawley rats fed chow ad libitum (control), a high calorie/carbohydrate diet, or a high fat (80%) diet for 7 weeks. Immunoblotting revealed that GLUT4 protein levels decreased 34% in high fat-fed rats, but were unaltered in high calorie/carbohydrate-fed obese rats compared to control values. GLUT4 mRNA per DNA decreased 47% in muscle of high fat-fed rats compared to that in control or high calorie-fed rats; GLUT1 mRNA was reduced 31%, and actin mRNA tended to decrease (29%). To assess GLUT4 and GLUT1 expression in genetic obesity, similar studies were carried out in 5- and 20-week-old lean and obese Zucker rats as well as in 20-week-old obese Zucker rats 36 h after streptozotocin injection to lower insulin levels. GLUT4 protein and mRNA levels were unaltered in hindlimb muscle of obese Zucker rats at either age or in the acutely diabetic state, whereas GLUT1 protein and mRNA levels decreased 40-45%. Comparison of these results with recent data in adipocytes demonstrates tissue-specific regulation of expression of GLUT4 and GLUT1. Thus, obesity due to high fat feeding, but not that due to high calorie/carbohydrate feeding or genetics, is associated with pretranslational suppression of GLUT4 expression in skeletal muscle. In at least some forms of obesity, the level of GLUT4 expression in muscle appears to be only one factor in, or may even be unrelated to, the degree of insulin-responsive glucose transport in vivo.
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PMID:Suppression of GLUT4 expression in skeletal muscle of rats that are obese from high fat feeding but not from high carbohydrate feeding or genetic obesity. 841 18

Insulin rapidly represses expression of the gene encoding the insulin-responsive glucose transporter (GLUT4) in 3T3-L1 mouse adipocytes. Upon exposure to the hormone the cellular level of GLUT4 mRNA falls (t1/2 approximately 2.5 hr) to 20-30% of its initial level within 10 hr. This is followed by a similar decrease in the level of GLUT4 protein. Down-regulation of GLUT4 mRNA is a result of both rapid repression of transcription of the GLUT4 gene and an increased rate of turnover of the GLUT4 message. As a consequence of prolonged exposure to insulin, 3T3-L1 adipocytes lose their capacity for acute stimulation of hexose uptake by insulin. These findings provide an explanation for the resistance of glucose uptake to insulin in adipose tissue observed in non-insulin-dependent (type 2) diabetes mellitus, particularly that associated with hyperinsulinemia and obesity.
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PMID:Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. 842 83

We have found that women with polycystic ovary syndrome (PCOS) have decreased sensitivity and responsiveness to insulin. The present study was performed to determine whether this impaired insulin responsiveness was associated with diminished GLUT-4 glucose transporter content in adipocytes. Insulin-stimulated glucose transport and GLUT-4 abundance were measured in abdominal adipocytes from obese (n = 9) and lean (n = 7) PCOS as well as obese (n = 8) and lean (n = 8) control women matched for age and weight. No woman had impaired glucose tolerance. The maximal insulin-stimulated increment in adipocyte glucose transport was independently decreased by obesity and by PCOS. As expected, GLUT-4 content in adipocyte membranes was decreased in obesity (by 40%, P < or = 0.01). GLUT-4 content was also significantly decreased in PCOS (by 36%, P < or = 0.01), independent of obesity. There was a highly significant correlation (R = 0.66, P < = 0.001) between GLUT-4 content and insulin-stimulated glucose transport in adipocytes from individual women across the study population. We conclude that the diminished adipocyte insulin responsiveness in PCOS is associated with decreased GLUT-4 abundance. This represents a newly recognized phenotypic feature of the insulin resistance of PCOS. Moreover, in human adipocytes, GLUT-4 abundance is highly correlated with insulin responsiveness.
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PMID:Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. 844 86

The purpose of this study was to determine the effects of chronic hyperglycemia and/or exercise training on the muscle concentration of the insulin-responsive glucose transporter protein, GLUT4, and on maximally insulin-stimulated hindlimb muscle glucose transport. Five-wk-old lean and obese Zucker rats were randomly assigned to sham-operated control (CTL) or 90% pancreatectomized (PX) groups. Obese-PX animals were further randomized into sedentary or exercise trained groups (15-wk treadmill running for 2 h.d-1, 5 d.wk-1, 15% grade, at 15-18 m.min-1). Muscle GLUT4 protein content and maximally insulin-stimulated glucose transport were determined in gastrocnemius, plantaris, and soleus muscles. At 20 wk, lean-PX displayed mild fasting hyperglycemia but normal insulin levels. Obese-PX rats had insulin levels similar to lean-CTL rats but had severe hyperglycemia. Hyperglycemia in lean-PX was associated with a 28% decrease in maximal glucose transport and a 65% decrease in muscle GLUT4 (P < 0.05) compared with lean-CTL. In obese-PX, maximal glucose transport was not affected, but muscle GLUT4 was reduced by 62% (P < 0.05) compared to obese-CTL. Exercise training obese-PX reduced hyperglycemia, increased maximal glucose transport by 45%, and increased muscle GLUT4 by > 2-fold (P < 0.05) compared with obese-CTL. Thus, hyperglycemia associated with PX may be an important factor in the reduction of muscle GLUT4 levels in lean and obese rats. The reduced GLUT4 was accompanied by reduced maximal glucose transport in lean but not obese rats. Exercise training reduced hyperglycemia, normalized glucose transport, and increased muscle GLUT4 in obese-PX.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glycemia and exercise training alter glucose transport and GLUT4 in the Zucker rat. 845 49


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