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)

Epidemiological studies have correlated diets containing higher intakes of PUFA with lower rates of chronic metabolic diseases. The molecular mechanisms regulated by the consumption of PUFA were examined by using an integrative metabolism approach assaying the liver transcriptome and lipid-metabolome of mice fed a control diet, an arachidonate (AA)-enriched fungal oil, an eicosapentaenoic (EPA)/docosahexaenoic (DHA)-enriched fish oil, or a combination of the two oils. Hepatic gene transcription and fatty acid (FA) metabolism were significantly altered by diets enriched with AA, as revealed by global error assessment and singular value decomposition (SVD) analysis, respectively. SVD analysis of the lipid data, reinforced with transcriptomics, suggests that the chronic feeding of AA modulates molecular endpoints similar to those previously reported in the obesity-resistant SCD1-/- mouse, namely, genes involved in lipid oxidation/synthesis and the significant changes in FA metabolism stemming from a repressed SCD1 activity. Specifically, the total levels and FA composition of several phospholipid (PL) species were significantly changed, with phosphatidylcholine (PC) demonstrating the greatest alterations. Reduced PC levels were linked to decreased expression of enzymes in PC biosynthesis (choline kinase, -2.2-fold; glycerol-3-phosphate acyltransferase, -2.0-fold). Alterations in PL-FA composition were related to decreased expression of FA biosynthetic genes [fatty acid synthetase, -3.7-fold; stearoyl-CoA desaturase-1 (SCD1), -1.8-fold]. Lower hepatic SCD1 gene expression levels were reflected in various aspects of FA metabolism through increased concentrations of palmitic (fungal oil, +45%; combination, +106%) and stearic acids (fungal oil, +60%; combination, +63%) in PC. Importantly, an integrated approach showed that these effects were not attenuated by the addition of an EPA/DHA-enriched fish oil, thereby identifying a previously unrecognized and distinct role for AA in the regulation of hepatic lipid metabolism.
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PMID:An integrative metabolism approach identifies stearoyl-CoA desaturase as a target for an arachidonate-enriched diet. 1567 Sep 75

To test whether long-chain fatty acyl-CoA esters link obesity with type 2 diabetes through inhibition of the mitochondrial adenine nucleotide translocator, we applied a system-biology approach, dual modular kinetic analysis, with mitochondrial membrane potential (Deltapsi) and the fraction of matrix ATP as intermediates. We found that 5 mumol/l palmitoyl-CoA inhibited adenine nucleotide translocator, without direct effect on other components of oxidative phosphorylation. Indirect effects depended on how oxidative phosphorylation was regulated. When the electron donor and phosphate acceptor were in excess, and the mitochondrial "work" flux was allowed to vary, palmitoyl-CoA decreased phosphorylation flux by 38% and the fraction of ATP in the medium by 39%. Deltapsi increased by 15 mV, and the fraction of matrix ATP increased by 46%. Palmitoyl-CoA had a stronger effect when the flux through the mitochondrial electron transfer chain was maintained constant: Deltapsi increased by 27 mV, and the fraction of matrix ATP increased 2.6 times. When oxidative phosphorylation flux was kept constant by adjusting the rate using hexokinase, Deltapsi and the fraction of ATP were not affected. Palmitoyl-CoA increased the extramitochondrial AMP concentration significantly. The effects of palmitoyl-CoA in our model system support the proposed mechanism linking obesity and type 2 diabetes through an effect on adenine nucleotide translocator.
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PMID:Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. 1579 31

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.
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PMID:Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. 1587 74

An imbalance between triacylglycerol synthesis and breakdown is necessary for the development of obesity. The direct precursor for triacylglycerol biosynthesis is alpha-glycerol phosphate, which can have glycolytic and glyceroneogenic origins. We present a technique for determining the relative glyceroneogenic contribution to triacylglyceride glycerol by labeling the glycerol moiety with 2H2O. The number of hydrogen atoms (n) incorporated from H2O into C-H bonds reflects the metabolic source of alpha-glycerol phosphate and can be calculated by combinatorial analysis of the distribution of mass isotopomers in triacylglyceride glycerol. Three physiological settings with potential effects on glyceroneogenesis and glycolysis were studied in rodents. Adipose tissue acylglyceride glycerol in mice fed a low carbohydrate diet had significantly higher values of n than in mice fed a high carbohydrate diet, suggesting an increased contribution from glyceroneogenesis of from 17 to 50% on the low carbohydrate diet. Similarly, mice administered rosiglitazone had a significant relative increase in glyceroneogenesis (from 17 to 53%), indicated by an increase in adipose acylglyceride glycerol n. Fructose infusion in overnight fasted rats rapidly lowered plasma triacylglyceride glycerol n, reflecting a decreased contribution from glyceroneogenesis (from 66 to 34%) presumably because of increased glycolytic input. In conclusion, we demonstrate that the number of C-H atoms derived from cellular H2O in triacylglyceride glycerol is an informative indicator of alpha-glycerol phosphate origin and, ultimately, triacylglycerol metabolism. Under certain physiological conditions, glyceroneogenesis can be up-regulated in adipose (e.g. low carbohydrate diet) or down-regulated in liver (e.g. fructose infusion). Additionally, stimulation of glyceroneogenesis by rosiglitazone in adipose tissue may be an important factor in the antilipolytic actions of thiazolidinediones.
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PMID:Physiologic and pharmacologic factors influencing glyceroneogenic contribution to triacylglyceride glycerol measured by mass isotopomer distribution analysis. 1588 53

Leptin, a hormone produced by the adipose tissues, reduces appetite and food intake, and increases energy expenditures by sending signals to the brain cells. As human obesity is associated with hyperleptinemia and increased systemic oxidative stress, we investigated whether leptin affects lipid peroxidation and antioxidant status in the brain. Leptin was intraperitoneally administered to adult male BALB/c mice (n = 6) at a dose of 40 mug/animal for 5 days, while control mice (n = 6) received phosphate buffered saline. All animals were decapitated one hour after the last injection, and the brain tissues were removed. Total brain tissues were homogenized with phosphate buffered saline. Lipid hydroperoxide and glutathione levels were measured by enzyme immunoassays. Data were statistically analysed by using Mann Whitney's U-test. Lipid hydroperoxide levels were significantly higher in the brain tissue of leptin-treated mice (3.44 +/- 0.36 nmol/g tissue, mean +/- S.E.M.) than those of the control mice (2.20 +/- 0.38 nmol/g tissue, p < 0.01). In contrast, leptin-treated mice had significantly lower glutathione levels in the brain tissue compared to the control (12.97 +/- 1.32 and 17.91 +/- 0.82 nmol/g tissue, respectively, p < 0.05). These results indicate that exogenous leptin increases lipid peroxidation and inhibits antioxidant system in the mouse brain. We therefore suggest that leptin may augment oxidative stress in the brain.
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PMID:Exogenous leptin increases lipid peroxidation in the mouse brain. 1594 50

Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver.
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PMID:Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. 1622 56

Obesity has become one of the most serious public health problems affecting both the developed and developing countries today. Obesity develops as a result of the positive energy balance. Therefore the strategies in obesity prevention and management are targeted on the energy balance. Dietary weight management should be focussed on the reduction of fat intake as fat among the three macronutrients exhibits the highest energy density and the lowest satiating properties as well as the lowest postprandial thermogenesis. Although carbohydrate does not play such an important role in the pathogenesis of obesity as fat, the intake of simple carbohydrate should be reduced during the treatment of obesity and metabolic syndrome. Different metabolic consequences of the intake of individual fatty acids (polyunsaturated and n-3 fatty acids vs. saturated fatty acids), individual carbohydrates (low vs. high glycaemic index carbohydrates) and fibre should be considered during the weight management. Dietary protein positively affects the outcome of weight management through the enhancement of postprandial satiety and thermogenesis. Recently a role of consumption of calcium, phosphate and vitamin A in the body weight regulation and weight management has been also studied.
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PMID:[Role of nutritional factors in the weight management]. 1638 64

The polyol isomalt (Palatinit) is a well established sugar replacer. The impact of regular isomalt consumption on metabolism and parameters of gut function in nineteen healthy volunteers was examined in a randomised, double-blind, cross-over trial with two 4-week test periods. Volunteers received 30 g isomalt or 30 g sucrose daily as part of a controlled diet. In addition to clinical standard diagnostics, biomarkers and parameters currently discussed as risk factors for CHD, diabetes or obesity were analysed. Urine and stool Ca and phosphate excretions were measured. In addition, mean transit time, defecation frequency, stool consistency and weight were determined. Consumption of test products was affirmed by the urinary excretion of mannitol. Blood lipids were comparable in both phases, especially in volunteers with hyperlipidaemia, apart from lower apo A-1 (P=0.03) for all subjects. Remnant-like particles, oxidised LDL, NEFA, fructosamine and leptin were comparable and not influenced by isomalt. Ca and phosphate homeostasis was not affected. Stool frequency was moderately increased in the isomalt phase (P=0.006) without changes in stool consistency and stool water. This suggests that isomalt is well tolerated and that consumption of isomalt does not impair metabolic function or induce hypercalciuria. In addition, the study data indicate that isomalt could be useful in improving bowel function.
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PMID:Effects of isomalt consumption on gastrointestinal and metabolic parameters in healthy volunteers. 1619 83

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 beta-HSD1 would be metabolically interconnected with the cytosolic pentose pathway because this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 beta-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 beta-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 beta-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter the tandem microsomal 11 beta-HSD1 and hexose-6-phosphate dehydrogenase enzyme unit. Metabolites of 11 beta-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 beta-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we have demonstrated a metabolic interconnection between pentose pathway and 11 beta-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.
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PMID:Evidence that the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is regulated by pentose pathway flux. Studies in rat adipocytes and microsomes. 1623 47

We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and insulin resistance). We had demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial type. We have shown that VC is worsened by CKD and ameliorated by bone morphogenetic protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein receptor null animals without CKD have hyperphosphatemia led us to examine the skeletons of these mice. We found significant reductions in bone formation rates, associated with increased VC and superimposing CKD results in the adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia persisted. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia, compatible with BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone formation and skeletal deposition of phosphate, and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury before demonstrable hyperphosphatemia, and they are preventable and treatable. Therefore, early intervention in CKD is warranted and may affect mortality of the disease.
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PMID:Connections between vascular calcification and progression of chronic kidney disease: therapeutic alternatives. 1633 68


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