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

Visceral obesity in man is followed by several abnormalities in endocrine secretions, including an elevated cortisol secretion as well as hyperandrogenicity in women, and a relative hypogonadism in men, suggesting a central neuroendocrine background. A pronounced insulin resistance is a main symptom of this condition and may be at least partially following these endocrine abnormalities. For example, mimicking hyperandrogenicity in women by administration of testosterone (T) in moderate doses to female rats is followed by severe muscular insulin resistance, as well as a low type I/type II muscle fiber ratio, and a low capillary density in muscle. These findings are identical to those in visceral obese women with hyperandrogenicity and insulin resistance. Studies of details of function and morphology in the muscles in this rat model have revealed that insulin stimulation of glucose transport, glycogen synthesis and the insulin sensitive part of the glycogen synthase is diminished at submaximal insulin concentrations. However, insulin receptor number and function, as well as the total number of glucose transporter 4 appear to be normal, supported by observations that the insulin resistance is overcome by elevated insulin concentrations. These observations suggest that normal cellular mechanisms for glucose metabolism in muscle in this model are under-utilized, and that the explanation to apparent insulin resistance may be found proximal to the machinery of the muscle cell. The histochemical changes of the muscles may provide a clue to the understanding of the mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin resistance: the consequence of a neuroendocrine disturbance? 755 May 39

1. The anti-obesity and anti-diabetic effects of mazindol were evaluated in obese diabetic yellow KK mice and C57Bl control mice. 2. The study compound was fed through a gastric tube at a rate of 1 or 2 mg/kg per day (0.01 mol/L HCl as control) for 2 weeks. The following parameters were compared in treated and control animals: bodyweight, food intake, white adipose tissue (WAT) weight, brown adipose tissue (BAT) weight and its thermogenesis, noradrenaline (NA) turnover, blood glucose and serum insulin levels and glucose transporter 4 (GLUT4). 3. Furthermore, bodyweight loss of mice pair-fed the same amount of food as the mazindol-treated mice for 2 weeks was measured. 4. Mazindol significantly decreased food intake and significantly increased guanosine-5'-diphosphate-binding in BAT mitochondria and NA turnover in BAT in both yellow KK and C57Bl groups. The amounts of WAT in subcutaneous, mesenteric and retroperitoneal regions and bodyweights were significantly decreased in both groups. Bodyweight loss in mice pair fed with the mazindol-treated groups was approximately 70% compared with that in the mazindol-treated groups. Furthermore, mazindol decreased the levels of blood glucose and serum insulin during the glucose overloading test in yellow KK mice, but it did not influence the GLUT4 protein concentration in WAT and muscle. 5. These observations suggest that mazindol possesses both an anti-obesity action, due to the inhibition of appetite as well as the activation of BAT thermogenesis via increased NA turnover in BAT, and an anti-diabetic action. Consequently, mazindol may be useful for the treatment of obesity as well as non-insulin-dependent diabetes mellitus in obese persons.
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PMID:Anti-obesity and anti-diabetic effects of mazindol in yellow KK mice: its activating effect on brown adipose tissue thermogenesis. 880 May 69

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
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PMID:Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. 915 Jun 93

The mechanism of insulin resistance in obesity is not fully understood. In muscle cells, the number of insulin receptor, the function of glucose transporter 4 and the activity of tyrosine kinase decrease. The rink of body fat accumulation and insulin resistance in muscle is thought through free fatty acid and tumor necrosis factor alpha secreted in adipose tissue. Thiazolidinediones (TZDs) are useful to reduce insulin resistance especially in obesity. TZDs seem to cause small weight gain, but to reduce visceral fat in 12-24 weeks. In longer period, it hasn't been studied very much. There are some unsolved problems. So now, targets of TZDs are obese diabetes failed in other medicines. When using TZDs, be cautious of excess eating and physical inactivity.
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PMID:[Obesity, insulin resistance and the implication of thiazolidinediones]. 1070 67

To determine possible genetic influences on the steady-state concentrations of several key transcription factor transcripts and the transcript concentrations for adipocyte-characteristic proteins, young, genetically obese and lean pigs were given ad libitum access or feed or were restrictively fed at 50% of ad libitum intake for 5 wk. Obese pigs were smaller and fatter than lean pigs, whether intake was ad libitum or restrictive. Plasma protein, albumin, and cholesterol concentrations were greater in obese than in lean pigs. Plasma NEFA, blood urea nitrogen, triacylglycerols, and postprandial glucose and insulin concentrations were less (P < .02) in pigs fed restrictively than in pigs with ad libitum access to feed, regardless of genetic group. The adipose tissue glucose transporter 4, fatty acid synthase, and leptin transcript concentrations were greater (P < .05) in obese than in lean pigs. The CCAAT/enhancer binding proteins beta and alpha, adipocyte fatty acid binding protein, hormone-sensitive lipase, and the beta1-adrenergic receptor transcript concentrations tended (P < . 10) to be greater in adipose tissue from obese than in that from lean pigs. Several other transcripts were numerically greater in obese than in lean pigs. The data collectively suggest that messenger RNA concentration for several adipose tissue proteins is a contributing factor to the excess fat deposition in these obese pigs. Restricted feeding did not change the concentration of any transcript except that for adipocyte fatty acid binding protein, which was reduced. The accretion of fat was markedly reduced in the restrictively fed pigs, but this diminution does not seem to be regulated by modulation of messenger RNA concentration.
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PMID:Effect of feed restriction on adipose tissue transcript concentrations in genetically lean and obese pigs. 1078 83

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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PMID:Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. 1101 58

Adipose tissue expresses a variety of genes including tumor necrosis factor alpha and type-1 plasminogen activator inhibitor (PAI-1); and these factors, produced by adipocytes, may be associated with the risk of coronary events in obesity. In this study, we characterized the production of fibrinolytic factors including tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PAI-1 in the differentiation of preadipocytes, and examined the hormonal regulation of these fibrinolytic factors in mature adipocytes. Mouse 3T3-L1 preadipocytes were employed as a model of adipocytes. Adipocyte differentiation was induced by insulin, dexamethasone, and 3-isobutyl-1-methyl xanthine (IBMX). alpha-Glycerophosphate dehydrogenase (GPDH) activity and glucose transporter 4 (GLUT4) mRNA, indices for adipocyte maturation, were induced on Day 4, and gradually increased. GPDH activity reached its maximum level on Day 14. The level of tPA, a major PA in preadipocytes, dramatically decreased with differentiation. On the other hand, that of uPA reciprocally increased. PAI-1 production was also dramatically induced concomitant with differentiation. In mature adipocytes, uPA production was dominant (25 microg/ml/24 h vs. 0.8 microg/ml/24 h for tPA). Total PA activity in the mature adipocytes was reduced by insulin or dexamethasone, but not by glucagon. Insulin, IBMX, and dexamethasone significantly decreased both uPA and tPA production, and increased PAI-1 production. Glucagon had no effect on the production of these fibrinolytic factors. Our results reveal that uPA is one of the markers for the differentiation of 3T3-L1 cells and that insulin, IBMX, and dexamethasone are potent regulators of the fibrinolytic activity in differentiated 3T3-L1 cells, reciprocally affecting PA and PAI-1 levels in them.
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PMID:Reciprocal regulation of tissue-type and urokinase-type plasminogen activators in the differentiation of murine preadipocyte line 3T3-L1 and the hormonal regulation of fibrinolytic factors in the mature adipocytes. 1157 6

Obesity is a major risk factor for the development of insulin resistance, characterized by impaired stimulation of glucose disposal into muscle. The mechanisms underlying insulin resistance are unknown. Here we examine the direct effect of leptin, the product of the obesity gene, on insulin-stimulated glucose uptake in cultured rat skeletal muscle cells. Preincubation of L6 myotubes with leptin (2 or 100 nM, 30 min) had no effect on basal glucose uptake but reduced insulin-stimulated glucose uptake. However, leptin had no effect on the insulin-induced gain in myc-tagged glucose transporter 4 (GLUT4) appearance at the cell surface of L6 myotubes. Preincubation of cells with leptin also had no effect on insulin-stimulated tyrosine phosphorylation of insulin receptor, IRS-1 and IRS-2, phosphatidylinositol 3-kinase activity, or Akt phosphorylation. We have previously shown that insulin regulates glucose uptake via a signaling pathway sensitive to inhibitors of p38 MAP kinase. Here, leptin pretreatment reduced the extent of insulin-stimulated p38 MAP kinase phosphorylation and phosphorylation of cAMP response element binder, a downstream effector of p38 MAP kinase. These results show that high leptin levels can directly reduce insulin-stimulated glucose uptake in L6 muscle cells despite normal GLUT4 translocation. The mechanism of this effect could involve inhibition of insulin-stimulated p38 MAP kinase and GLUT4 activation.
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PMID:High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells. 1160 47

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.
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PMID:Pro-inflammatory cytokines and adipose tissue. 1168 9

The human insulin-responsive glucose transporter 4 gene (GLUT4) has been related to non-insulin-dependent diabetes mellitus (NIDDM) in several studies. Obesity is commonly found in patients with NIDDM. Hence, genes involved in NIDDM might also be relevant for obesity. We have analyzed 212 extremely obese children and adolescents, 82 normal-weight students, and 94 underweight students for two single nucleotide polymorphisms (SNPs: promoter -30G/A; exon 4a: silent 2061T/C) in the vicinity of the GLUT4 by polymerase chain reaction with subsequent restriction fragment length polymorphism analyses (PCR-RFLP) or single-strand conformation polymorphism analyses (SSCP). Allele and genotype distributions were similar in all study groups (all p values > 0.05). Hence, we did not detect association of any of the analyzed SNP alleles in the GLUT4 to different weight extremes, so these seem not to be involved in weight regulation in our study groups.
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PMID:Glucose transporter 4 gene: association studies pertaining to alleles of two polymorphisms in extremely obese children and adolescents and in normal and underweight controls. 1207 88


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