Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All cells must maintain a high ratio of cellular ATP:ADP to survive. Because of the adenylate kinase reaction (2ADP <--> ATP + AMP), AMP rises whenever the ATP:ADP ratio falls, and a high cellular ratio of AMP:ATP is a signal that the energy status of the cell is compromised. The AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is switched on by a rise in the AMP:ATP ratio, via a complex mechanism that results in an exquisitely sensitive system. AMPK is switched on by cellular stresses that either interfere with ATP production (e.g. hypoxia, glucose deprivation, or ischemia) or by stresses that increase ATP consumption (e.g. muscle contraction). It is also activated by hormones that act via Gq-coupled receptors, and by leptin and adiponectin, via mechanisms that remain unclear. Once activated, the system switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes that are not essential for short-term cell survival, such as the synthesis of lipids, carbohydrates, and proteins. The AMPK cascade is the probable target for the antidiabetic drug metformin, and current indications are that it is responsible for many of the beneficial effects of exercise in the treatment and prevention of type 2 diabetes and the metabolic syndrome.
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PMID:Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. 1296 15

Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.
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PMID:[The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism]. 1450 Nov 64

Genome-wide scanning is a powerful tool to identify susceptible chromosome loci, however, individual chromosomal regions still have many candidate genes. Although cDNA microarray analysis provides valuable information for identifying genes involved in pathogenesis, expression levels of many genes are changed. A novel approach for identification of therapeutic targets is the combination of genome-wide scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we screened for secreted molecules, the expressions of which were changed in adipose tissues from mice rendered insulin resistance. Decreased expression of one of these molecules, adiponectin/Acrp30, correlates strongly with insulin resistance. Interestingly, recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where adiponectin gene is located. Decreasing serum adiponectin levels are associated with increased risk for type 2 diabetes. Interestingly, adiponectin was decreased in insulin resistant rodent models both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated their insulin resistance. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes Adiponectin knockout mice showed insulin resistance and glucose intolerance. In muscle and liver, adiponectin activated AMP kinase and PPARalpha pathways thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated insulin resistance under a high-fat diet. Despite similar plasma glucose and lipid levels on an apoE deficient background, adiponectin transgenic apoE deficient mice showed amelioration of atherosclerosis, which was associated with decreased expressions of class A scavenger receptor and tumor necrosis factor alpha. Finally, cDNA encoding adiponectin receptors (AdipoR1 and R2) have been identified by expression cloning, which facilitates the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and R2 as molecular targets.
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PMID:Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. 1468 55

Metabolic syndrome is a pathophysiological state in which risks for atherosclerosis are clustered. Etiology of metabolic syndrome is multi-factorial. Excess energy intake causes imbalance of energy transcription factors such as PPARs and SREBP-1c, which are deeply involved in lipid and carbohydrate metabolism, leading to insulin resistance and dyslipidemia. Especially hepatic SREBP-1c could be involved in production of remnant lipoproteins, fatty liver, and hepatic insulin resistance. Meanwhile, currently, therapeutic trend is activation of energy expenditure, in which PPAR alpha, delta, and AMP kinase are current targets of treatment. Proinflammatory agents should also be involved and adipocytokines could play an important role in peripheral insulin resistance.
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PMID:[Pathophysiology of metabolic syndrome]. 1520 38

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

The 5' AMP-activated protein kinase (AMPK) is a sensor of cellular energy homeostasis well conserved in all eukaryotic cells. AMPK is activated by rising AMP and falling ATP, either by inhibiting ATP production or by accelerating ATP consumption, by a complex mechanism that results in an ultrasensitive response. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta. Once activated, it switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis) both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Dominant mutations in the regulatory gamma subunit isoforms cause hypertrophy of cardiac and skeletal muscle providing a link in human diseases caused by defects in energy metabolism. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of adipokines such as leptin and adiponectin. Moreover, the AMPK system is one of the probable target for the anti-diabetic drug metformin and rosiglitazone. The relationship between AMPK activation and beneficial metabolic effects provides the rationale for the development of new therapeutic strategies. Thus, pharmacological AMPK activation may, through signaling, metabolic and gene expression effects, reduce the risk of Type 2 diabetes, metabolic syndrome and cardiac diseases.
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PMID:[Regulation of energy metabolism by AMPK: a novel therapeutic approach for the treatment of metabolic and cardiovascular diseases]. 1659 7

Rat offspring prenatally exposed to alcohol display features of metabolic syndrome characterized by a low birth weight, catch-up growth, dyslipidemia, and insulin-resistant diabetes with increased gluconeogenesis, during adult life. Gluconeogenesis is partly regulated by cyclic AMP- and glucocorticoid-dependent mechanisms. Glucocorticoid action at the receptor level depends on its circulating concentrations and is amplified at the prereceptor level by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms. To determine whether 11beta-HSD1 is dysregulated in this rat model, we examined the expression and enzyme activity of 11beta-HSD1 and its regulator enzyme hexose-6-phosphate dehydrogenase (H6PD) in the liver of postnatal day 7 (neonatal) and 3-mo-old (adult) rat offspring prenatally exposed to alcohol. Measurements of 11beta-HSD1 and H6PD were also performed in the omental fat of adult rat offspring. In both neonatal and adult rats, prenatal alcohol exposure resulted in increased tissue corticosterone concentrations, increased expression, and oxoreductase activity of 11beta-HSD1, and a parallel increase of H6PD expression. The data suggest that due to both transcriptional and posttranscriptional dysregulations, rats exposed to alcohol early in life have increased 11beta-HSD1 activity, which may explain insulin-resistant diabetes in these animals later in life.
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PMID:Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero. 1712 34

The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.
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PMID:AMP-activated protein kinase in metabolic control and insulin signaling. 1730 71

In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.
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PMID:Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. 1799 41

The MS (metabolic syndrome) is a cluster of clinical and biochemical abnormalities characterized by central obesity, dyslipidaemia [hypertriglyceridaemia and decreased HDL-C (high-density lipoprotein cholesterol)], glucose intolerance and hypertension. Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. This review focuses on lipid metabolism alterations associated with the MS, paying special attention to changes in plasma lipids and cellular fatty acid oxidation. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. Activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. Decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS.
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PMID:Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome. 1818 12


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