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)

To examine whether fatty acid transport is abnormal in obesity, the kinetics of [3H]oleate uptake by hepatocytes, cardiac myocytes, and adipocytes from adult male Wistar (+/+), Zucker lean (fa/+) and fatty (fa/fa), and Zucker diabetic fatty (ZDF) rats were studied. A tissue-specific increase in oleate uptake was found in fa/fa and ZDF adipocytes, in which the Vmax was increased 9-fold (p < 0.005) and 13-fold (p < 0.001), respectively. This increase greatly exceeded the 2-fold increase in the surface area of adipocytes from obese animals, and did not result from trans-stimulation secondary to increased lipolysis. Adipocyte tumor necrosis factor-alpha mRNA levels, assayed by Northern hybridization, increased in the order +/+ < fa/fa < ZDF. Oleate uptake was also studied in adipocytes from 20-24-day-old male +/+, fa/+, and fa/fa weanlings. These animals were not obese, and had equivalent plasma fatty acid and glucose levels. Tumor necrosis factor-alpha mRNA levels in +/+ and fa/fa cells also were similar. Nevertheless, Vmax was increased 2.9-fold (p < 0.005) in fa/fa compared +/+ cells. These studies indicate 1) that regulation of fatty acid uptake is tissue-specific and 2) that up-regulation of adipocyte fatty acid uptake is an early event in Zucker fa/fa rats. These findings are independent of the role of any particular fatty acid transporter. Adipocyte mRNA levels of three putative transporters, mitochondrial aspartate aminotransferase, fatty acid translocase, and fatty acid transporting protein (FATP) were also determined; mitochondrial aspartate aminotransferase and FATP mRNAs correlated strongly with fatty acid uptake.
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PMID:Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of Zucker rats with genetic obesity and non-insulin-dependent diabetes mellitus. 907 20

Obese hypertensive patients with cardiovascular risk factor clustering have increased plasma nonesterified fatty acid levels and are at high risk for atherosclerotic events. Our previous studies demonstrated that oleic acid induces a mitogenic response in rat aortic smooth muscle cells (RASMCs) through protein kinase C (PKC)- and extracellular signal-regulated kinase (ERK)-dependent pathways. In the present study we investigated the possibility that the generation of reactive oxygen species (ROS) constitutes a critical component of the oleic acid-induced mitogenic signaling pathway in RASMCs. We studied the effect(s) of oleic acid on the generation of ROS using the oxidant-sensitive fluoroprobe 2',7'-dichlorofluorescin diacetate. Relative fluorescence intensity and fluorescent images were obtained with laser confocal scanning microscopy from 1 to 5 minutes, since preliminary studies demonstrated that the peak fluorescence intensity occurred within 5 minutes. Oleic acid (100 micromol/L) induced a time-dependent increase of cell fluorescence that was >8-fold of that seen in control cells at 5 minutes. This was blocked by catalase, which suggests that H2O2 was the principal ROS. The oleic acid-induced increases in H2O2 were blocked when PKC was inhibited with the use of bisindolylmaleimide and when PKC activity was downregulated by exposing RASMCs to phorbol 12-myristate 13-acetate for 24 hours. Stearic and elaidic acids, which are weak PKC activators, did not significantly increase H2O2 production. The increase of H2O2 in response to oleic acid was inhibited by the antioxidant N-acetylcysteine. N-Acetylcysteine also completely blocked ERK activation and the increase of thymidine incorporation in response to oleic acid. The data suggest that generation of H2O2 in RASMCs exposed to oleic acid is PKC dependent. Moreover, H2O2 production emerges as a critical intermediary event in the oleic acid-mediated mitogenic signaling pathway between the activation of PKC and ERK. These observations raise the possibility that the elevated plasma nonesterified fatty acids, including oleic acid, in obese hypertensive patients contribute to vascular growth and remodeling by a PKC-dependent mechanism to generate ROS that subsequently activate ERK.
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PMID:Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. 985 64

Cells take up long chain free fatty acids (FFA) in vivo from the non-protein bound ligand pools in extracellular fluid and plasma, which contain approximately 100 and 600 microM albumin, respectively. The physiologic range of unbound FFA concentrations in such fluids has traditionally been calculated at <1 microM. Studies of [3H]-oleate uptake by hepatocytes, adipocytes, cardiac myocytes and other cell types demonstrate that FFA uptake within this range is saturable, and exhibits many other kinetic properties indicative of facilitated transport. Within this range, the uptake kinetics of the acidic (pKa = 0.5) FFA analog alpha2,beta2,omega3-heptafluorostearate are similar to those of stearate. Thus, uptake of physiologic concentrations of FFA involves facilitated transport of the FFA anion (FA). Over a much wider range of unbound FFA concentrations hepatocellular [3H]-oleate uptake exhibits both saturable and non-saturable components. Oleate binding to liver plasma membranes (LPM) also demonstrates such components. Comparing the two components of FFA uptake to the corresponding components of binding permits estimates of trans-membrane transport rates. T1/2 for saturable uptake (approximately 1 sec) is less than for non-saturable uptake (approximately 14 sec). Others have determined the flip-flop rates of protonated FFA (FAH) across small and large unilamellar vesicles (SUV, LUV) and across cellular plasma membranes. These reported flip-flop rates, measured by the decrease in pH resulting from the accompanying proton flux, exhibit a highly significant inverse correlation with cell and vesicle diameter (r = 0.99). Although T1/2's in vesicles are in the msec range, those in cells are >10 sec, and thus comparable to the rates of non-saturable uptake we determined. Thus, under physiologic conditions, the predominant mechanism of cellular FFA uptake is facilitated transport of FA ; at much higher, non-physiologic FFA concentrations, passive flip-flop of FAH predominates. Several plasma membrane proteins have been identified as potential mediators of facilitated FFA transport. Studies in animal models of obesity and non-insulin dependent diabetes mellitus demonstrate that tissue-specific regulation of facilitated FFA transport has important pathophysiologic consequences.
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PMID:Mechanisms of cellular uptake of long chain free fatty acids. 1033 55

To better understand the link between fatty acid signaling and the pleiotropic effects of fatty acids in the pancreatic beta-cell, we investigated whether fatty acids regulate immediate-early response genes (IEGs) coding for transcription factors implicated in cell proliferation, differentiation, and apoptosis. Palmitate and oleate, but not long-chain polyunsaturated fatty acids, caused a pronounced accumulation of c-fos and nur-77 mRNAs in beta-cells (INS cells) to an extent similar to that produced by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). The effect was dose dependent and occurred at concentrations between 0.1 and 0.5 mmol/l in the presence of 0.5% albumin. The action of the fatty acid occurred at the transcriptional level, and the mRNA accumulation displayed a bell-shaped kinetics with a maximal effect at 1 h. 2-Bromopalmitate was ineffective, indicating that fatty acids must be metabolized to cause their effect. Neither fatty acid was able to induce c-fos and nur-77 in PKC-downregulated cells or cells incubated in the presence of the Ca2+ channel blocker nifedipine or the Ca2+ chelator EGTA, suggesting involvement of the PKC and Ca2+ signaling pathways. Palmitate and oleate also increased c-fos protein expression and DNA binding activity of the transcription factor AP-1. Oleate, but not palmitate, increased [3H]thymidine incorporation in INS cells. Finally, both palmitate and oleate caused c-fos and nur-77 mRNA accumulation in isolated rat islets. It is suggested that IEG induction by the most abundant circulating fatty acids plays a role in the adaptive process of the beta-cell to hyperlipidemia. These results have implications for our understanding of obesity-associated diabetes and the link between fatty acids and tumorigenesis.
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PMID:Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS-1. 1051 66

We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Delta = 13.5 +/- 3.6 microg/dl; P < 0.05) and NE (Delta = 235 +/- 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 +/- 35 vs. 112 +/- 13 and 106 +/- 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 +/- 13 (oleate) vs. 135 +/- 20 (caprylate) and 96 +/- 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.
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PMID:Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation. 1109 16

Stearoyl-CoA desaturase (SCD) is a regulatory enzyme in lipogenesis, catalyzing the rate-limiting step in the overall de novo synthesis of monounsaturated FA, mainly oleate and palmitoleate from stearoyl- and palmitoyl-CoA, respectively. Oleate and palmitoleate are the major monounsaturated FA of membrane phospholipids, TG, wax esters, cholesterol esters, and alkyldiacylglycerol. Several SCD gene isoforms (SCD1, SCD2, SCD3, and SCD4) exist in mice, and two have been characterized in humans. SCD1 gene expression in liver cells is regulated by numerous stimuli including diet and hormones. We are interested in why SCD is such a highly regulated enzyme even though oleate, the major product of this enzyme, is one of the most abundant FA in the diet and is therefore readily available. Dietary oleate is also well known for its TG-lowering effects and, as a major component of olive oil, is expected to have beneficial effects. However, high SCD activity has been implicated in diabetes, obesity, atherosclerosis, and cancer in several animal models; therefore, the role that de novo oleate plays in these disease states has to be carefully evaluated. By using SCD1-/- mice, which are deficient in tissue oleate, we begin to learn more about the physiological role of SCD gene expression and oleate in normal and disease states.
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PMID:Regulation of stearoyl-CoA desaturase expression. 1572 20

Relative increases in unsaturated fatty acids (USFA) in the diet are considered to exert beneficial effects on coronary risk factors (CRF). However, detailed analysis of the relationships between serum USFA and CRF are scanty and there is no report of the relationship between nervonic acid (NA) and CRF. The objective of the present study was to analyze the relationships between serum USFA and CRF. Body height and weight, blood pressure, fasting serum total cholesterol (TC), triacyl-glycerol (TG), HDL cholesterol (HDLc), fasting blood sugar (FBS), total fatty acid composition, leptin, and high-sensitivity C-reactive protein (CRP) were measured in 31 men (age, 41-78 years) and 11 women (age, 54-77 years). The relationships between serum USFA, and body mass index (BMI), leptin, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, HDLc, FBS, and CRP were analyzed using multiple regression analysis. The final results were summarized using coronary risk factor scores (CRFS) in order to assess the correlations between USFA with CRF. Oleic acid (OA), linoleic acid (LA), and eicosapentaenoic acid (EPA) were positively related to coronary risk factors (total CRFS = 2, 3, and 4, respectively), while nervonic acid (NA) exerted negative effects on these risk factors (total CRFS = -6 ). It is concluded NA may have preventive effects on obesity-related metabolic disorders.
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PMID:Relationships between serum unsaturated fatty acids and coronary risk factors: negative relations between nervonic acid and obesity-related risk factors. 1639 93

Exogenous FA cause lipid accumulation in pre-adipocytes. We investigated whether the fat cells thus formed are metabolically distinct from adipocytes differentiated with standard methylisobutylxanthine, dexamethasone, and insulin (MDI) hormonal cocktail by comparing their expression of adipogenic genes, accumulation of TAG, lipogenesis, lipolysis, glucose uptake, and the effects of insulin on selected metabolic activities. Cells exposed to oleate began to accumulate TAG in parallel or prior to the induction of adipogenic genes, whereas cells treated with MDI expressed adipogenic genes before TAG accumulation. Oleate-treated fat cells also showed exaggerated basal lipolysis and weak response to insulin in both lipolysis regulation and glucose uptake. These findings were associated with increased basal phosphorylation of perilipin, increased Glut-1 but decreased Glut-4 expression, and reduced insulin-induced Akt phosphorylation. We suggest that this unique fat cell phenotype might be a mimetic of what can happen to fat cells formed in vivo under the influence of circulating FA and might be a useful model for in vitro studies of obesity-related insulin resistance in adipocytes.
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PMID:Oleate-induced formation of fat cells with impaired insulin sensitivity. 1671 1

The elevation of free fatty acids (FFAs), observed in childhood obesity results in intramyocellular lipid (IMCL) accumulation with consequent insulin resistance. Using in vitro differentiated myotubes from normal weight pre-pubertal children (n = 8), we examined the effects of saturated (palmitate) and unsaturated (oleate) FFAs on insulin-stimulated AKT phosphorylation (pAKT) and IMCL accumulation. Palmitate decreased pAKT (Mean [SEM] % change pAKT with palmitate 750 microM vs. control; pThr308 site -50.5% [28.7] and pSer473 site -38.7% [11.7]; P < 0.001) with no effect on IMCL formation. Equimolar bromopalmitate did not effect pAKT and blocking ceramide production abolished the palmitate-induced reduction in signalling, suggesting that ceramide synthesis is critical for palmitate's actions. Oleate did not effect pAKT (1,000 microM oleate; pSer473 site -3.4% [11.4]; P = NS) but increased IMCL accumulation (+32.3% [7.1%]; P < 0.001). Co-administration of oleate diminished the reduction in pAKT seen with palmitate (+36.4% [23.6] vs. -13.3% [13.6]; P = 0.28), with similar IMCL levels to oleate alone. Co-administration also caused a significant reduction in 14C-ceramide synthesis from 14C-palmitate (101.6 [21.6] vs. 371.5 [122.4] DPM/mg protein; P < 0.001). In summary, palmitate appears to cause insulin resistance in children's myotubes via its metabolism to ceramide, and this process appears unrelated to IMCL formation and is ameliorated by oleate.
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PMID:Fatty acid-induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid. 1721 4

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.
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PMID:Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats. 1755 Mar 47


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