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

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine secretion or the adipocyte-specific gene expression is one of the most important targets for the prevention of obesity and amelioration of insulin sensitivity. In this study, we demonstrated that anthocyanins (cyanidin or cyanidin 3-glucoside) have the potency of a unique pharmacological function in isolated rat adipocytes. Treated adipocytes with anthocyanins enhanced adipocytokine (adiponectin and leptin) secretion and up-regulated the adipocyte specific gene expression without activation of PPARgamma in isolated rat adipocytes. The gene expression of adiponectin was also up-regulated in white adipose tissue in mice fed an anthocyanin supplemented diet. As one of the possible mechanisms, AMP-activated protein kinase activation would be associated with these changes, nevertheless, the AMP:ATP ratio was significantly decreased by administration of the anthocyanins. These data suggest that anthocyanins have a potency of unique therapeutic advantage and also have important implications for preventing obesity and diabetes.
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PMID:Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. 1500 23

The pharmacological treatment options for obesity are currently very limited but the prevalence of the disease is increasing rapidly. Obesity has many serious sequelae, the most common of which is type-2-diabetes. The benefits of weight loss on health are established but the major impediment to weight loss treatments is maintenance of weight lost over the long term. The reduced- or post-obese individual undergoes physiological changes that are geared towards energy storage and weight regain. One of the physiological changes is a reduced capacity to oxidise fatty acids pushing them through pathways of triacylglycerol synthesis. In this review, some of the past drug treatments aimed at increasing energy expenditure, such as dinitrophenol and ephedrine. are discussed. Current, or nearly current therapies such as sibutramine and rimonabant are also discussed in the context of increased energy expenditure. The main part of the review focuses on future prospects with discussion around a selection of targets with potential in energy expenditure that lie in pathways with AMP-kinase at their centre and ending at the mitochondrion.
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PMID:Treating obesity: pharmacology of energy expenditure. 1505 15

New evidence suggests that leptin and other anorexigenic agents reduce appetite by inactivating hypothalamic AMP-activated protein kinase (AMPK), thereby increasing malonyl CoA levels. This preview examines AMP biology and its role in malonyl-CoA generation and attempts to integrate its central actions with its peripheral antilipotoxic actions within the context of leptin physiology in obesity.
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PMID:The hyperleptinemia of obesity-regulator of caloric surpluses. 1508 51

The modulation of fatty acid metabolism and especially the stimulation of fatty acid oxidation in liver or skeletal muscle are attractive therapeutic approaches for the treatment of obesity and the associated insulin resistance. However, current beta-oxidation assays are run in very low throughput, which represents an obstacle for drug discovery in this area. Here we describe results for a 48-well beta-oxidation assay using a new instrument design. A connecting chamber links two adjacent wells to form an experimental unit, in which one well contains the beta-oxidation reaction and the other captures CO(2). The experimental units are sealed from each other and from the outside to prevent release of radioactivity from the labeled substrate. CO(2) capture in this instrument is linear with time and over the relevant experimental range of substrate concentration. Cellular viability is maintained in the sealed environment, and cells show the expected responses to modulators of beta-oxidation, such as the AMP kinase activator 5-aminoimidazole carboxamide riboside. Data are presented for different lipid substrates and cell lines. The increased throughput of this procedure compared with previously described methods should facilitate the evaluation of compounds that modulate fatty acid metabolism.
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PMID:A self-contained 48-well fatty acid oxidation assay. 1509 Feb 11

Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported previously that AdipoR1 and -R2 serve as receptors for adiponectin and mediate increased fatty acid oxidation and glucose uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of AdipoR1/R2 in vivo. Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo. Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide 3-kinase/Foxo1-dependent pathway in vitro. Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue, which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice. In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.
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PMID:Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. 1512 5

Obesity and insulin resistance have been recognised as leading causes of major health issues, particularly diabetes type 2 and metabolic syndrome. Although obesity, defined as excess body fat, is frequently accompanied by insulin resistance, diabetes, metabolic syndrome and cardiovascular diseases, the molecular basis for the link between obesity and those diseases has not yet been clarified. Adipose tissue expresses various secretory proteins, including leptin, tumour necrosis factor-alpha and adiponectin, which may be involved in the regulation of energy expenditure, lipid metabolism and insulin resistance. The aim of this study is to provide an overview of the metabolic alterations occurring in insulin resistance as well as to review the biological roles of adiponectin, particularly in the regulation of fatty acid oxidation and insulin action. Adiponectin is the most abundant gene product in adipose tissue and accounts for 0.01% of total plasma protein. Plasma adiponectin level is decreased in obesity, both in children and adults, and it is negatively associated to plasma insulin and positively associated to plasma triglycerides. Low levels of adiponectin decreases fatty acid oxidation in muscle. Recent data have demonstrated that adiponectin effects are mediated by the interaction with muscle and hepatic receptors through activation of AMP kinase, the cellular "fuel gauge", which in turn inhibits acetyl CoA carboxylase and increases fatty acid beta-oxidation. Since there is no available recombinant adiponectin for human use, its direct effects on human metabolism remain unknown, but this hormone appears to be promising in the treatment of obesity an related metabolic disorders.
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PMID:Adiponectin, the missing link in insulin resistance and obesity. 1538 Aug 84

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.
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PMID:Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. 1593 75

Metabolism cycles daily between the fed and fasted states. The pathways of energy production are reversible and distinct. In the anabolic (fed) state, the liver stores glucose as glycogen, and fatty acid/triglyceride synthesis is active. In the catabolic (fasted) state, the liver becomes a glucose producer, lipogenesis is slowed, and fatty acid oxidation/ketogenesis is activated. The rate-limiting step for the latter is vested in the carnitine/carnitine palmitoyltransferase (CPT) system, and the off/on regulator of this is malonyl CoA. The AMP-induced protein kinase primarily determines the concentration of malonyl CoA. Four other systems have significant influence: two on fatty acid oxidation and two on lipogenesis. Peroxisome proliferator-activated receptor gamma-1 alpha, a master regulator of metabolism, induces hepatic gluconeogenesis and fatty acid oxidation in the catabolic phase. Deficiency of stearoyl CoA desaturase, although having no role in gluconeogenesis, powerfully induces fatty acid oxidation and weight loss despite increased food intake in rodents. Major stimulators of lipogenesis are carbohydrate-responsive element binding protein and the Insig system. The malonyl CoA-regulated CPT system has been firmly established in humans. The other systems have not yet been confirmed in humans, but likely are active there as well. Activation of fatty acid oxidation has considerable clinical promise for the treatment of obesity, type 2 diabetes, steatohepatitis, and lipotoxic damage to the heart.
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PMID:The role of the carnitine system in human metabolism. 1559 Sep 99

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

The MC3R and MC4R proteins comprise two melanocortin receptor subtypes that are involved in obesity, with each protein displaying a unique mechanism of action. To enable the design of a selective drug candidate, the solution structures of four peptidyl analogues of the melanocyte stimulating hormones, NDP-MSH, NDP-MSH(4-10) and two cyclic forms ([C5,C10]NDP-MSH(5-10), [C5,C10]NDP-MSH(5-11)), were characterized by two-dimensional nuclear magnetic resonance (NMR) spectroscopy and simulated annealing calculations. Using data from c-AMP assays in combination with structural analysis of melanocortin receptor/ligand models, we conclude that a lysine residue at the C-terminus of the His-Phe-Arg-Trp core sequence of melanocortin hormone is an important determinant for receptor selectivity in the both cyclic and linear MSH analogues. Our results suggest that side-chain orientation and charge-charge interactions with the ligand molecule play critical roles in receptor selectivity, whereas the overall backbone conformation or turn type contributes mainly to receptor binding.
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PMID:Structure and function of the potent cyclic and linear melanocortin analogues. 1589 Feb 78


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