Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Obesity is known to be associated with insulin resistance in human and rat adipocytes. However, it is not known what are the perturbations in insulin action that contribute to disproportional femoral obesity. Thus femoral subcutaneous adipose tissue was obtained from lean women with various degrees of disproportional obesity, by liposuction. 3-O-methylglucose (3-O-methyl-D-glucopyranose) transport was measured in intact cells, and glucose transporter levels in plasma and low-density microsomal membranes were assessed using the cytochalasin B binding assay. A sixfold cellular enlargement was associated with increase in both basal and insulin-stimulated glucose transport activity in the intact cell, and a 300-600% increase in insulin stimulating effect per se. However, when glucose transporter levels were assessed, this cellular enlargement was accompanied by a 40-70% transporter depletion (in largest cells compared with smallest ones) in both subcellular fractions examined, from either basal or insulin-stimulated cells. This discrepancy, between increasing cellular glucose transport rates and relative depletion of transporter levels, suggests that these cells are not insulin resistant, as could be expected from their large size. A role for other factor(s), additional to glucose transporter levels, in the regulation of cellular glucose uptake rate is thus suggested.
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PMID:Discrepancy between glucose transport and transporters in human femoral adipocytes. 264 41

The mechanism for enhanced metabolism of inhaled anesthetics in obese rats and humans is unknown. In this study, hepatic microsomes from normal-weight chow-fed rats and rats fed a high fat diet for approximately 54 weeks to induce obesity were examined for their ability to metabolize fluorinated inhalation anesthetics. Body composition of rats on diet for 54 weeks revealed a significantly elevated lipid content of both the whole body and liver in obese compared to normal-weight rats. Protein per g liver was not significantly different. The hepatic microsomal content of cytochromes b5 and P-450 per mg protein was not different between obese and normal-weight rats. Hepatic microsomal defluorination rates of the anesthetics, methoxyflurane, enflurane and isoflurane, were not altered by high fat diets of 54 weeks duration. The activity rate of aminopyrine N-demethylase was not changed by the diet; however, p-nitroanisole O-demethylase activity was significantly increased in microsomes from obese rats to approximately 150% of control activity. Thus the enhanced in vivo anesthetic metabolism of obese Fischer 344 rats does not appear to be the result of an increase in the specific activity of anesthetic metabolizing enzymes.
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PMID:In vitro hepatic drug and anesthetic metabolism of rats with dietary-induced obesity. 277 69

Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes. 305 97

Liver microsomes from obese and control Sprague-Dawley rats were compared for cytochrome P-450 content and the ability to metabolize various prototype substrates. Over a 40-week period, the obesity-producing energy-dense diet increased average total body mass by 50%, liver mass by 32%, and body fat mass by 292%. Spectrally detectable cytochrome P-450 per mg protein increased by 36% in hepatic microsomes from obese rats. The livers from obese rats also contained more cytochrome P-450 (87%), while microsomal protein, NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase, and UDP-glucuronosyl transferase per organ rose slightly (12-40%) but not significantly. No change in the specific activities of these enzymes occurred. Young and adult rats were transferred from pellet diet to energy-dense diet for 3 weeks to examine the influence of diet vs. obesity. This short-term dietary change increased microsomal protein per g liver as well as cytochrome P-450 per liver, per g liver, and per mg protein. Adult animals increased in body weight by 24%, making them overweight and borderline obese. However, young animals showed no increase in body or liver weight, suggesting a direct effect of the energy-dense diet on liver P-450. Dietary obesity thus increased both the relative and total amounts of liver cytochrome P-450 in rats, but not the specific activities of other enzymes. These changes in cytochrome P-450 are consistent with the increased clearance seen for several oxidized drugs in obese humans and suggest that the obese overfed rat represents a useful animal model.
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PMID:Hepatic cytochrome P-450 and in vitro drug metabolism in an overfed rat model of obesity. 314 37

The obese overfed rat effectively models many of the pharmacological changes in human obesity. Recent data show that the obese rat is unusually susceptible to liver damage by several metabolically activated drugs that may be more toxic in obese humans. Results of the present study suggest a specific molecular locus for this interaction. In obese rats, P450 content of liver and the microsomal concentration of P450 were elevated 88% and 31%, respectively, over nonobese controls. Increases in microsomal ethanol oxidation were of identical magnitude. The ethanol-inducible form of P450 that is responsible for microsomal ethanol oxidation, P450IIE1, bioactivates several drugs that are shown to cause increased injury in obese rats. Collectively, these findings indicate that specific forms of P450 may become up-regulated in obesity, increasing the risk of a biochemically defined spectrum of drug-induced organ injuries.
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PMID:Obesity as a risk factor for drug-induced organ injury. VI. Increased hepatic P450 concentration and microsomal ethanol oxidizing activity in the obese overfed rat. 319 41

Hydroxymethylglutaryl coenzyme A reductase (HMGR) activity is a major factor in the regulation of cholesterol homeostasis. Enzyme activity is known to vary with age, sex, diurnal cycle, and dietary properties in rats. Mice are available in numerous genetic strains and could be a useful inexpensive animal model for studying diet and genetic interactions in the regulation of cholesterol metabolism. Obese and non-obese C57BL/6J, CBA/J, and obese and non-obese DW dbPas mice were subjected to variations in light cycle, feeding schedule, and pectin and fat composition of their diets. They were then killed by decapitation, and hepatic microsomal HMGR analyzed. The mice responded in the same ways as rats to light cycle, feeding pattern, and sex difference. They exhibited marked differences in HMGR activity due to age, genotype, strain, and diet variations. We conclude that mice will, indeed, offer an excellent animal model for the study of cholesterol metabolism regulation.
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PMID:Hepatic hydroxymethylglutaryl coenzyme A reductase activity in inbred strains of mice. 323 19

The anorectic drug D-fenfluramine (D-F) was administered as single i.v. doses of 1.25 and 6.25 mg/kg to lean female Sprague-Dawley and lean and obese female Zucker rats. Blood samples were collected serially and analysed by electron capture gas-liquid chromatography for D-F and its main metabolite, D-norfenfluramine (D-NF). At the lowest dose the disappearance of D-F followed an apparent first-order process with mean elimination half-life (T1/2) of approximately 2 h in female Sprague-Dawley and 4 h in lean and obese Zucker rats. Mean absolute steady-state volume of distribution (Vss) was the same in the lean female of both strains but total clearance (Cl) was significantly lower in the Zucker rats. Therefore elimination T1/2 of D-F was longer in female Zucker than Sprague-Dawley animals. Obese rats presented lower relative Cl and Vss but no change in absolute Cl and Vss and elimination T1/2 of the drug. Intra- and inter-strain differences were observed in hepatic microsomal protein and P-450 content. As in the case of D-F the elimination T1/2 of D-NF was also longer in Zucker than Sprague-Dawley rats. No differences were observed between lean and obese rats but in all cases the elimination T1/2 of the metabolite was much longer than that of its parent drug. After larger doses (6.25 mg/kg) the kinetics of the drug were not linear. The apparent Cl declined changing the metabolite-to-parent drug ratios in all types of rats, but more evidently in Zucker than Sprague-Dawley rats and in obese than lean animals. Inter- and intra-strain differences in D-F and D-NF kinetics should be considered in neurochemical studies of the drug and extrapolation of data across animal species requires consideration of dose dependence in the rat.
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PMID:Disposition of D-fenfluramine in lean and obese rats. 335 26

To examine the role of glucose transport proteins in cellular insulin resistance, we studied subcutaneous adipocytes isolated from lean control, obese control (body mass index [BMI] 33.4 +/- 0.9), and untreated obese non-insulin-dependent diabetes mellitus (NIDDM) patients (BMI 35.2 +/- 2.1; fasting glucose 269 +/- 20 mg/dl). Glucose transporters were measured in plasma membrane (PM), low-density (LDM), and high-density (HDM) microsomal subfractions from basal and maximally insulin-stimulated cells using the cytochalasin B binding assay, and normalized per milligram of membrane protein. In all subgroups, insulin led to an increase in PM glucose transporters and a corresponding depletion of transporters in the LDM. Insulin recruited 20% fewer transporters to the PM in the obese subgroup when compared with lean controls, and this was associated with a decline in LDM transporters with enlarging cell size in the control subjects. In NIDDM, PM, and LDM, transporters were decreased 50% in both basal and stimulated cells when compared with obese controls having similar mean adipocyte size. Cellular depletion of glucose transporters was not the only cause of insulin resistance, because the decrease in rates of [14C]-D-glucose transport (basal and insulin-stimulated) was greater than could be explained by reduced numbers of PM transporters in both NIDDM and obesity. In HDM, the number of transporters was not influenced by insulin and was similar in all subgroups. We conclude that (a) in NIDDM and obesity, both reduced numbers and impaired activity of glucose transporters contribute to cellular insulin resistance, and (b) in NIDDM, more profound cellular insulin resistance is associated primarily with a further depletion of cellular transporters.
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PMID:Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. 336 6

Obese and lean male Zucker rats were fed ad libitum on diets containing either 50 (L) or 200 (H) g/kg diet of either triolein (T) or sunflowerseed oil (S). The specific activity of the hepatic microsomal delta 9 desaturase enzyme was depressed in both lean and obese rats fed the HS diet compared with the other three diets. The fatty acid composition of liver and subcutaneous white adipose tissue lipids were consistent with a lower delta 9 desaturation activity in rats fed the H diets, particularly for the HS diet. In both genotypes, microsomal delta 9 desaturase activity and the ratio of 16:1/(16:0 + 16:1) fatty acids in liver lipids were inversely related to the proportion of 18:2 in liver lipid. Plasma insulin concentrations and rates of glucose-stimulated insulin release in vivo were higher in obese rats compared with lean rats, and plasma insulin levels were higher in rats fed S compared with T. There was no relationship between delta 9 desaturase activity and either plasma insulin concentration or rates of insulin release in vitro. These findings suggest that hepatic delta 9 desaturase activity of Zucker rats is responsive to changes in the proportion of 18:2 in liver lipids but is not affected by changes in insulin secretion.
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PMID:Effects of dietary triolein and sunflower oil on insulin release and lipid metabolism in Zucker rats. 351 42

We examined insulin's effects on glucose transport and on subcellular transporter distribution in isolated human omental adipocytes of various sizes. Insulin stimulated 3-O-methylglucose transport by twofold in small cells, while a smaller and insignificant effect was measured in large cells. In the small cells, basal concentrations of glucose transporters were 2.9 and 17.2 pmol/mg membrane protein in the plasma and the low density microsomal membranes, respectively. Increasing cell size was associated with a 50% decrease in the concentration of transporters in each fraction, with no change in their total number per cell. Insulin stimulated the translocation of transporters from the intracellular pool to the plasma membranes, irrespective of cell size. Thus, insulin resistance at the postreceptor level, observed in human obesity, may be associated with a relative depletion of total transporters per cell together with a reduction in their intrinsic activity at the plasma membrane level.
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PMID:Distribution of glucose transporters in membrane fractions isolated from human adipose cells. Relation to cell size. 353 Dec 36


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