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)

There is a conserved mechanism in all living organisms whereby overnutrition negatively regulates lifespan, while loss of function mutations in the genes encoding insulin/IGF-1 signaling molecules also independently shorten lifespan in worms and flies. However, in mammals, same mutations sometimes result in severe metabolic disorders and shorter lifespan, although knockout mice with disruption of some insulin/IGF-1 signaling molecules display prolonged lifespan. Moreover, obesity-induced diabetes and metabolic syndrome are also associated with shorter lifespan despite the decreased insulin signaling in liver and skeletal muscle. This is presumably because hyperinsulinemia in obese animals and humans enhances insulin signaling in particular tissues which determine aging and longevity. It is also likely that overnutrition suppresses AMP kinase and increase mTOR activity, contributing to the shorter lifespan in obese subjects.
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PMID:[The mechanisms whereby insulin/IGF-1 signaling regulates aging and longevity]. 1959 Dec 78

The AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. As the name suggests, the AMPK is activated by increased intracellular concentrations of AMP, and is generally described as a "metabolite-sensing kinase" and when activated initiates steps to conserve cellular energy. Although there is a strong link between the activity of the AMPK and metabolic control in muscle cells, the activity of the AMPK in endothelial cells can be regulated by stimuli that affect cellular ATP levels, such as hypoxia as well as by fluid shear stress, Ca(2+)-elevating agonists, and hormones such as adiponectin. To date the AMPK in endothelial cells has been implicated in the regulation of fatty acid oxidation, small G protein activity and nitric oxide production as well as inflammation and angiogenesis. Moreover, there is evidence indicating that the activation of the AMPK may help to prevent the vascular complications associated with the metabolic syndrome.
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PMID:Activation and signaling by the AMP-activated protein kinase in endothelial cells. 1960 89

The metabolic syndrome, a cluster of conditions including abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure, is a natural consequence of over nutrition and a sedentary lifestyle. The prevalence of the metabolic syndrome has increased to epidemic proportions in the world. The exact pathogenesis of the metabolic syndrome remains unclear, but it is known to be a complex interaction between genetic, metabolic, and environmental factors. Promotion of physical activity and dietary management are still the main methods for the prevention and management of the metabolic syndrome. Numerous experimental and clinical studies have demonstrated the beneficial effects of high fiber diet on the metabolic syndrome. The principal beneficial effects of a fiber-rich diet in these patients are: prevention of obesity, improved glucose levels, and control of the profile of blood lipids. Dietary fiber may also favor the control of arterial blood pressure. How dietary fiber exerts its beneficial effects on the metabolic syndrome is not well understood. AMP activated protein kinase (AMPK) functions as a major cellular fuel gauge and a master regulator of metabolic homeostasis. Several lines of evidence suggest that AMPK can be activated by short-chain fatty acids (SCFA) either directly or indirectly. It is our hypothesis that the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome is the increased SCFA production in the colon leading to a higher concentration of SCFA in the portal vein, which activates the AMPK in the liver.
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PMID:Activation of the AMP activated protein kinase by short-chain fatty acids is the main mechanism underlying the beneficial effect of a high fiber diet on the metabolic syndrome. 1966 12

Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. The functional capacity of the adipose tissue varies among subjects explaining the incomplete overlapping among the metabolic syndrome and obesity. Far turnover is determined by a complex equilibrium in which insulin is a main factor but not the only one. Chronically inadequate energy balance may be a key factor, stressing the system. In this situation, an adipose tissue functional failure occurs resulting in changes in systemic energy delivery, impaired glucose consumption and activation of self-regulatory mechanisms that extend their influence to the whole body homeostasis system. 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. The activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in the fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. A decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, the 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:[Adipokines and lipids]. 1970 16

AMP-activated protein kinase (AMPK) is considered an important target for treatment of type II diabetes and the metabolic syndrome. The muscle-specific isoform of the regulatory gamma-subunit, gamma 3, within the context of AMPK alpha 2 beta 2 gamma 3 complex, is involved in glucose and fat metabolism in skeletal muscle. In an effort to identify gamma 3-specific activators of AMPK, we have produced truncated human recombinant AMPK alpha 2 beta 2 gamma 3 (hu alpha 2 beta 2 gamma 3(trunc)) for biochemical characterization. Infection of insect cells with three baculoviral stocks encoding the individual subunits resulted in soluble expression of a stable hu alpha 2 beta 2 gamma 3(trunc) heterotrimeric complex. Co-expression of the three subunits was essential for solubility since the individual protein components, when expressed separately, were almost completely insoluble. The hu alpha 2 beta 2 gamma 3(trunc) heterotrimer was purified to apparent homogeneity from baculovirus-infected insect cells in a 1:1:1 stoichiometric complex. The hu alpha 2 beta 2 gamma 3(trunc) heterotrimer had significant circular dichroism signal that was lost as a function of temperature, implying that the purified protein was folded. The hu alpha 2 beta 2 gamma 3(trunc) complex was capable of binding AMP and ATP, although the heterotrimer showed preference for AMP, in particular, as seen by thermal denaturation circular dichroism analyses. Further experiments showed that the truncated complex bound ZMP (AICAR-monophosphate) albeit with much lower affinity than AMP. To investigate whether there were isoform-specific differences in the nucleotide binding affinities, a well-characterized truncated mammalian alpha 1 beta 2 gamma 1 (m alpha 1 beta 2 gamma 1(trunc)) equivalent of hu alpha 2 beta 2 gamma 3(trunc) was also purified. The gamma 1 and gamma 3 isoforms showed comparable nucleotide binding affinities and solution behavior properties.
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PMID:Purification and characterization of truncated human AMPK alpha 2 beta 2 gamma 3 heterotrimer from baculovirus-infected insect cells. 1983 52

Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
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PMID:Up-regulating the heme oxygenase system with hemin improves insulin sensitivity and glucose metabolism in adult spontaneously hypertensive rats. 2001 31

Unfavorable lipid accumulation may occur in the kidneys in the presence of metabolic syndrome and diabetes. The aim of this study was to investigate whether excess lipids would accumulate in the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of metabolic syndrome. From 34 weeks of age, OLETF rats were treated orally with a calcium channel blocker, benidipine (3 mg kg(-1) per day), or an AT1 receptor blocker, losartan (25 mg kg(-1) per day), for 8 weeks. Blood pressure was slightly but significantly higher in the untreated OLETF rats (149+/-4 mm Hg) than in Long-Evans Tokushima Otsuka (LETO) rats (136+/-2 mm Hg), and both losartan (135+/-3 mm Hg) and benidipine (138+/-3 mm Hg) reduced blood pressure in OLETF rats to a level comparable to that in LETO rats. Tissue content of triglycerides (TG) was greater in OLETF rats than in LETO rats (6.24+/-3.77 and 2.85+/-1.32 microg mg(-1) x tissue, respectively), and both losartan and benidipine reduced these values. Histological analysis showed lipid droplets in tubular cells in which increased dihydroethidium fluorescence was present. Expression of peroxisome proliferator-activated receptor-alpha, PGC-1alpha and uncoupling protein-2 was found to be higher in OLETF rats than in LETO rats; however, the expression of these genes was not altered by treatment with either antihypertensive drug. In contrast, both losartan and benidipine increased the amount of total and phosphorylated forms of AMP kinase and the expression of carnitine palmitoyltransferase-1 (CPT-1). In conclusion, treatment of OLETF rats with losartan and benidipine reduced the tissue content of TG, decreased the production of superoxide and regulated the expression of genes related to fatty acid oxidation such as AMP-activated protein kinase and CPT-1 in the kidneys.
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PMID:Effects of the AT(1) receptor blocker losartan and the calcium channel blocker benidipine on the accumulation of lipids in the kidney of a rat model of metabolic syndrome. 2005 86

Energy homeostasis and stress resistance are closely linked on aging and longevity. AMPK (AMP-activated protein kinase) is a sensor of cellular energy status activated by metabolic stress that accelerates AMP/ATP ratio, regulating cell polarity, metabolic homeostasis and sensitivity to stress resistance. AMPK could be therapeutic targets for cancer, diabetic mellitus and obesity, providing a possible link to metabolic syndrome. However, little is known how functional deficiency of AMPK affects longevity and stress resistance in vivo due to its redundancy and lethality in null-mutant. SNF1A/dAMPKalpha (CG3051) is a single orthologue for its mammalian counterparts in Drosophila melanogaster. Using time- and tissue-specific RNAi system in D. melanogaster, we found that adult-onset inhibition of dAMPKalpha especially in muscle shortens lifespan. In addition, inhibition of dAMPKalpha in muscle enhances sensitivity to paraquat and starvation stress. Real-time PCR analysis showed that inhibition of dAMPKalpha in muscle affected the transcriptional regulation of various genes in response to starvation. These results raise the possibility that muscle is one of major tissues in which AMPK plays a critical role on longevity and stress resistance and the intervention to activate AMPK in muscle could be a prominent treatment strategy for longevity.
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PMID:A critical role of SNF1A/dAMPKalpha (Drosophila AMP-activated protein kinase alpha) in muscle on longevity and stress resistance in Drosophila melanogaster. 2018 62

AMP-activated protein kinase (AMPK) is an energy-sensing serine/threonine protein kinase that plays a central role in whole-body energy homeostasis. AMPK is a heterotrimeric enzyme with a catalytic (alpha) subunit and two regulatory (beta and gamma) subunits. The muscle-specific AMPK heterotrimeric complex (alpha2beta2gamma3) is involved in glucose and fat metabolism in skeletal muscle and therefore has emerged as an attractive target for drug development for diabetes and metabolic syndrome. To date, expression of recombinant full-length human AMPK alpha2beta2gamma3 has not been reported. Here we describe the expression, purification and biochemical characterization of functional full-length AMPK alpha2beta2gamma3 heterotrimeric complex using an Escherichia coli expression system. All three subunits of AMPK alpha2beta2gamma3 were transcribed as a single tricistronic transcript driven by the T7 RNA polymerase promoter, allowing spontaneous formation of the heterotrimeric complex in the bacterial cytosol. The self-assembled trimeric complex was purified from the cell lysate by nickel-ion chromatography using the hexahistidine tag fused exclusively at the N-terminus of the alpha 2 domain. The un-assembled beta 2 and gamma 3 domains were removed by extensive washing of the column. Further purification of the heterotrimer was performed using size exclusion chromatography. The final yield of the recombinant AMPK alpha2beta2gamma3 complex was 1.1mg/L culture in shaker flasks. The E. coli expressed enzyme was catalytically inactive after purification, but was activated in vitro by upstream kinases such as CaMKKbeta and LKB1. The kinase activity of activated AMPK alpha2beta2gamma3 complex was significantly enhanced by AMP (an allosteric activator) but not by thienopyridone A-769662, a known small molecule activator of AMPK. Mass spectrometric characterization of recombinant AMPK alpha2beta2gamma3 showed significant heterogeneity before and after activation that could potentially hamper crystallographic studies of this complex.
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PMID:Escherichia coli expression, purification and characterization of functional full-length recombinant alpha2beta2gamma3 heterotrimeric complex of human AMP-activated protein kinase. 2045 17

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.
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PMID:Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK. 2050 76


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