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

C57BL/6J (B6) and AKR/J (AKR) inbred strains of mice develop a comparable degree of obesity when fed a high-fat diet. However, although obese B6 mice are more glucose intolerant, obese AKR mice are more insulin resistant. To understand the basis for these strain differences, we characterized features of adiposity and glucose homeostasis in mice fed a high-fat diet for 8 weeks. The results indicated that despite hyperglycemia and impaired glucose tolerance, B6 mice have lower plasma insulin and are more insulin sensitive than AKR mice. Compared with adipose tissue of AKR mice, adipose tissue of B6 mice contained about threefold higher levels of total membrane-bound GLUT4 protein, whereas in skeletal muscle the levels were similar. Uptake of 2-[(14)C]deoxyglucose in vivo was reduced by a high-fat diet in adipose tissue, but not in skeletal muscle. Surprisingly, no significant differences in uptake occurred between the strains, despite the differences in GLUT4; however, glucose flux was calculated to be slightly higher in B6 mice. Higher expression of PEPCK in the liver of B6 mice, under both standard-diet and high-fat-diet conditions, suggests a plausible mechanism for elevated glycemia in these mice. In conclusion, phenotypic variation in insulin resistance and glucose production in the B6 and AKR strains could provide a genetic system for the identification of genes controlling glucose homeostasis.
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PMID:Variation in type 2 diabetes--related traits in mouse strains susceptible to diet-induced obesity. 1288 11

The first inhibition study of the mitochondrial isozyme carbonic anhydrase (CA) V (of murine origin) with a series of aromatic and heterocyclic sulfonamides is reported. Inhibition data of the cytosolic isozymes CA I and CA II and the membrane-bound isozyme CA IV with these inhibitors are also provided for comparison. Several low nanomolar CA V inhibitors were detected (KI values in the range of 4-15 nM), most of them belonging to the acylated sulfanilamide, ureido-benzenesulfonamide, 1,3,4-thiadiazole-2-sulfonamide, and aminobenzolamide type of compounds. The clinically used inhibitors acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and topiramate on the other hand were less effective CA V inhibitors, showing inhibition constants in the range of 47-63 nM. Some of the investigated sulfonamides, such as the ureido-benzenesulfonamides and the acylated sulfanilamides showed higher affinity for CA V than for the other isozymes, CA II included, which is a remarkable result, since most compounds investigated up to now inhibited the cytosolic isozyme CA II better. These results prompt us to hypothesize that the selective inhibition of CA V, or the dual inhibition of CA II and CA V, may lead to the development of novel pharmacological applications for such sulfonamides, for example in the treatment or prevention of obesity, by inhibiting CA-mediated lipogenetic processes.
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PMID:Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. 1497 7

The accurate matching of caloric intake to caloric expenditure involves a complex system of peripheral signals and numerous CNS neurotransmitter systems. Syndecans are a family of membrane-bound heparan sulfate proteoglycans that modulate ligand-receptor interactions. Syndecan-3 is heavily expressed in several areas of the brain, including hypothalamic nuclei, which are known to regulate energy balance. In particular, syndecans have been implicated in modulation of the activity of the melanocortin system, which potently regulates energy intake, energy expenditure, and peripheral glucose metabolism. Our data demonstrate that syndecan-3-null mice have reduced adipose content compared with wild-type mice. On a high-fat diet, syndecan-3-null male and female mice exhibited a partial resistance to obesity due to reduced food intake in males and increased energy expenditure in females relative to that of wild-type mice. As a result, syndecan-3-null mice on a high-fat diet accumulated less adipose mass and showed improved glucose tolerance compared with wild-type controls. The data implicate syndecan-3 in the regulation of body weight and suggest that inhibition of syndecan-3 may provide a therapeutic approach for the treatment of obesity resulting from exposure to high-fat diets.
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PMID:Mice lacking the syndecan-3 gene are resistant to diet-induced obesity. 1552 Aug 68

Phosphoinositides are membrane-bound signaling molecules that recruit, activate and localize target effectors to intracellular membranes regulating apoptosis, cell proliferation, insulin signaling and membrane trafficking. The SH2 domain containing inositol polyphosphate 5-phosphatase-2 (SHIP2) hydrolyzes phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) generating phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2). Overexpression of SHIP2 inhibits insulin-stimulated phosphoinositide 3-kinase (PI3K) dependent signaling events. Analysis of diabetic human subjects has revealed an association between SHIP2 gene polymorphisms and type 2 diabetes mellitus. Genetic ablation of SHIP2 in mice has generated conflicting results. SHIP2 knockout mice were originally reported to show lethal neonatal hypoglycemia resulting from insulin hypersensitivity, but in addition to inactivating the SHIP2 gene, the Phox2a gene was also inadvertently deleted. Another SHIP2 knockout mouse has now been generated which inactivates the SHIP2 gene but leaves Phox2a intact. These animals show normal insulin and glucose tolerance but are highly resistant to weight gain on high fat diets, exhibiting an obesity-resistant phenotype. Therefore, SHIP2 remains a significant therapeutic target for the treatment of both obesity and type 2 diabetes.
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PMID:The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2. 1596 36

Cellular long-chain fatty acid (LCFA) uptake constitutes a process that is not yet fully understood. LCFA uptake likely involves both passive diffusion and protein-mediated transport. Several lines of evidence support the involvement of a number of plasma membrane-associated proteins, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and fatty acid transport protein (FATP). In heart and skeletal muscle primary attention has been given to unravel the mechanisms by which FAT/CD36 expression and function are regulated. It appears that both insulin and contractions induce the translocation of intracellular stored FAT/CD36 to the plasma membrane to increase cellular LCFA uptake. This review focuses on this novel mechanism of regulation of LCFA uptake in heart and skeletal muscle in health and disease. The distinct signaling pathways underlying insulin-induced and contraction-induced FAT/CD36 translocation will be discussed and a comparison will be made with the well-defined glucose transport system involving the glucose transporter GLUT4. Finally, it is hypothesized that malfunctioning of recycling of these transporters may lead to intracellular triacylglycerol (TAG) accumulation and cellular insulin resistance. Current data indicate a pivotal role for FAT/CD36 in the regulation of LCFA utilization in heart and skeletal muscle under normal conditions as well as during the altered LCFA utilization observed in obesity and insulin resistance. Hence, FAT/CD36 might provide a useful therapeutic target for the prevention or treatment of insulin resistance.
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PMID:Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. 1619 26

Reduced circulating levels of high density lipoprotein cholesterol (HDL-C) are a frequent lipoprotein disorder in coronary heart disease patients and can be caused by either genetic and/or environmental factors (sedentary lifestyle, diabetes mellitus, smoking, obesity or a diet enriched in carbohydrates). Extremely low serum HDL-C levels occur in patients with Tangier disease (TD), which is caused by mutations in the adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1). Clinical manifestations are related to the storage of cholesteryl esters in reticuloendothelial tissues and to peripheral neuropathy. This review focuses on the genetic and lipid abnormalities of TD, the consequence of these on clinical outcome and the possible treatment options. These abnormalities reflect the importance of HDL in the pathogenesis of vascular disease.
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PMID:Tangier disease four decades of research: a reflection of the importance of HDL. 1661 Oct 66

Oxidative stress may play a role in the pathogenic mechanism of essential hypertension. Lipid peroxidation can alter the cellular structure of membrane-bound enzymes by changing the membrane phospholipids fatty acids composition. We investigated the relationship between (Na + K)-ATPase activity, lipid peroxidation, and erythrocyte fatty acid composition in essential hypertension. The study included 40 essential hypertensive and 49 healthy normotensive men (ages 35-60 years). Exclusion criteria were obesity, dyslipidemia, diabetes mellitus, smoking, and any current medication. Patients underwent 24-h ambulatory blood pressure monitoring and blood sampling. Lipid peroxidation was measured in the plasma and erythrocytes as 8-isoprostane or malondialdehyde (MDA), respectively. Antioxidant capacity was measured as ferric reducing ability of plasma (FRAP) in the plasma and as reduced/oxidized glutathione (GSH/GSSG ratio) in erythrocytes. (Na + K)-ATPase activity and fatty acids were determined in erythrocyte membranes. Hypertensives had higher levels of plasma 8-isoprostane, erythrocyte MDA, and relative percentage of saturated membrane fatty acids, but lower plasma FRAP levels, erythrocyte GSH/GSSG ratio, (Na + K)-ATPase activity and relative percentage of unsaturated membrane fatty acids, compared with normotensives. Day-time systolic and diastolic blood pressures correlated positively with lipid peroxidation parameters, but negatively with (Na + K)-ATPase activity. These findings suggest that the modulation of (Na + K)-ATPase activity may be associated with changes in the fatty acid composition induced by oxidative stress and provide evidence of a role for this enzyme in the pathophysiology of essential hypertension.
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PMID:Relationship between (Na + K)-ATPase activity, lipid peroxidation and fatty acid profile in erythrocytes of hypertensive and normotensive subjects. 1741 Apr 6

Angiotensin II (Ang II) is able to induce free radical generation in neutrophils, which is more elevated in neutrophils of patients with hypercholesterolemia (HC). In addition, the signal processing through angiotensin I (Ang I) receptors is altered. In present study, we compared the Ang II-triggered free radical generation of neutrophils obtained from patients with relatively isolated forms of metabolic syndrome (MS) with membrane-bound cholesterol content and membrane fluidity. We determined the enhancement of Ang II-induced superoxide anion and leukotriene C(4) (LTC(4)) generation, membrane fluidity and cell-bound cholesterol content of neutrophils obtained from 12 control subjects, 11 patients with obesity (Ob), 10 patients with type 2 diabetes mellitus (t2-DM) and 12 patients with HC. The alteration of signal processing was studied after preincubation with different inhibiting drugs. Superoxide anion, LTC(4) production and membrane rigidity were increased in the following order: control < Ob < t2-DM < HC. Both Ang II-induced superoxide anion and LTC(4) generation were decreased in control cells by pertussis toxin and fluvastatin (Flu), whereas in each patient group, mepacrin, verapamil and Flu were effective, suggesting alterations in signal pathways, which may be attributed to isoprenylation. The enhancement of superoxide anion and LTC(4) generation correlated significantly with membrane rigidity, independently from the experimental groups and membrane-bound cholesterol content. Membrane rigidity of neutrophils, obtained from patients with MS, plays a role in Ang II-induced free radical generation independent of intracellular cholesterol homeostasis.
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PMID:The association between angiotensin II-induced free radical generation and membrane fluidity in neutrophils of patients with metabolic syndrome. 1754 12

While obesity has a high prevalence in developed countries, the routine abnormalities seen from the clinical biochemistry laboratory that may be caused by obesity related pathology do not seem to be as common. Insulin resistance, which is often associated with obesity, is difficult to assess as formal procedures are too complex for clinical practice. Furthermore the interpretation of insulin levels is hampered by their in vivo variability, assay differences and the lack of reference intervals from an unaffected reference population. Interpretation of fasting glucose levels between 5.5 and 6.0mmol/L are also being debated however, it is useful to understand the age related changes in this parameter, which may also be due to increasing obesity in the reference population. The association of obesity and dyslipidaemia in the metabolic syndrome should focus on elevated triglycerides (>1.5mmol/L), which is associated with low HDLC and correlates with atherogenic small dense LDL. High triglycerides are also predictive of fatty liver and the common abnormality of an elevated ALT may not be appreciated if laboratories allow their reference intervals to increase as the population gets more obese with aging. SHBG levels fall with insulin resistance/hyperinsulinaemia and this needs to be taken into account when testosterone is measured. However, low SHBG is showing huge potential as a disease and prognostic marker in obesity. These commonly available tests provide useful insights for the obese patient and their utility may improve with future research into the growing problem of obesity.
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PMID:The clinical biochemistry of obesity-more than skin deep. 1761 Nov 53

Soluble protein hormones are key regulators of a number of metabolic processes, including food intake and insulin sensitivity. We have used a signal sequence trap to identify genes that encode secreted or membrane-bound proteins in Psammomys obesus, an animal model of obesity and type 2 diabetes (T2D). Using this signal sequence trap, we identified the chemokine chemerin as being a novel adipokine. Gene expression of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), was significantly higher in adipose tissue of obese and type 2 diabetic P. obesus compared with lean, normoglycemic P. obesus. Fractionation of P. obesus adipose tissue confirmed that chemerin was predominantly expressed in adipocytes, whereas CMKLR1 was expressed in both adipocytes and stromal-vascular cells of adipose tissue. In 3T3-L1 adipocytes, chemerin was markedly induced during differentiation, whereas CMKLR1 was down-regulated during differentiation. Serum chemerin levels were measured by ELISA in human plasma samples from 114 subjects with T2D and 142 normal glucose tolerant controls. Plasma chemerin levels were not significantly different between subjects with T2D and normal controls. However, in normal glucose tolerant subjects, plasma chemerin levels were significantly associated with body mass index, circulating triglycerides, and blood pressure. Here we report, for the first time, that chemerin is an adipokine, and circulating levels of chemerin are associated with several key aspects of metabolic syndrome.
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PMID:Chemerin is a novel adipokine associated with obesity and metabolic syndrome. 1764 Sep 97


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