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)

Increasing evidence suggests that elevation of plasma fatty acids that often accompanies insulin resistance contributes to beta-cell insufficiency in obesity-related type 2 diabetes. Circulating levels of hepatocyte growth factor (HGF) are increased in humans with metabolic syndrome and obesity. HGF is known to protect beta-cells against streptozotocin and during islet engraftment. However, whether HGF is a beta-cell prosurvival factor in situations of excessive lipid supply has not been deciphered. Mice overexpressing HGF in the beta-cell [rat insulin type II promoter (RIP)-HGF transgenic mice] fed with standard chow display improved glucose homeostasis and increased beta-cell mass and proliferation compared with normal littermates. However, after 15 wk of high-fat feeding, glucose homeostasis and beta-cell expansion and proliferation are indistinguishable between normal and transgenic mice. Interestingly, RIP-HGF transgenic mouse beta-cells and normal beta-cells treated with HGF display increased sensitivity to palmitate-mediated apoptosis in vitro. Palmitate completely eliminates Akt and Bad phosphorylation in RIP-HGF transgenic mouse islets. HGF-overexpressing islets also show significantly decreased AMP-activated protein kinase-alpha and acetyl-coenzyme A carboxylase phosphorylation, diminished fatty acid oxidation, increased serine palmitoyltransferase expression, and enhanced ceramide formation compared with normal islets. Importantly, human islets overexpressing HGF also display increased beta-cell apoptosis in the presence of palmitate. Treatment of both mouse and human islet cells with the de novo ceramide synthesis inhibitors myriocin and fumonisin B1 abrogates beta-cell apoptosis induced by HGF and palmitate. Collectively, these studies indicate that HGF can be detrimental for beta-cell survival in an environment with excessive fatty acid supply.
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PMID:Novel proapoptotic effect of hepatocyte growth factor: synergy with palmitate to cause pancreatic {beta}-cell apoptosis. 2017 23

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

Apolipoprotein A-I (ApoA-I) is the most abundant protein constituent of high-density lipoprotein (HDL). Reduced plasma HDL and ApoA-I levels have been found to be associated with obesity and metabolic syndrome in human beings. However, whether or not ApoA-I has a direct effect on obesity is largely unknown. Here we analysed the anti-obesity effect of ApoA-I using two mouse models, a transgenic mouse with overexpression of ApoA-I and the mice administered with an ApoA-I mimetic peptide D-4F. The mice were induced to develop obesity by feeding with high fat diet. Both ApoA-I overexpression and D-4F treatment could significantly reduce white fat mass and slightly improve insulin sensitivity in the mice. Metabolic analyses revealed that ApoA-I overexpression and D-4F treatment enhanced energy expenditure in the mice. The mRNA level of uncoupling protein (UCP)1 in brown fat tissue was elevated by ApoA-I transgenic mice. ApoA-I and D-4F treatment was able to increase UCP1 mRNA and protein levels as well as to stimulate AMP-activated protein kinase (AMPK) phosphorylation in brown adipocytes in culture. Taken together, our results reveal that ApoA-I has an anti-obesity effect in the mouse and such effect is associated with increases in energy expenditure and UCP1 expression in the brown fat tissue.
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PMID:Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat. 2019 37

AMP-activated protein kinase (AMPK) has been proposed as a therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. The bioassay-guided fractionation of an EtOAc-soluble extract of the stem bark of Erythrina abyssinica led to the isolation of a new coumestan, erythribyssin N (1), and two new benzofurans, erythribyssin F (2) and erythribyssin H (3), along with five known compounds (4-8). When tested for their stimulatory effects on AMPK activity at a concentration of 10 muM, compounds 4 and 5 showed potent activation, while compounds 1, 2, and 7 had moderate effects. These results suggest that benzofurans and coumestans may be new lead compounds for regulating the AMPK enzyme.
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PMID:AMP-activated protein kinase (AMPK) activation by benzofurans and coumestans isolated from Erythrina abyssinica. 2033 86

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed.
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PMID:The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. 2041 85

Adiponectin is an adipocytokine involved in the pathogenesis of various obesity-related disorders. Also, it has been shown that adiponectin has therapeutic potential for metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. Adiponectin can modulate breast cancer cell growth and proliferation. Anti-metastatic effects of adiponectin have also been elucidated. It has been shown that adiponectin inhibits important metastatic properties such as adhesion, invasion and migration of breast cancer cells. Examination of the underlying molecular mechanisms has shown that adiponectin treatment increases AMP-activated protein kinase (AMPK) phosphorylation and activity. Adiponectin also increases phosphorylation of downstream target of AMPK, Acetyl-CoA Carboxylase (ACC) and decreases phosphorylation of p70S6 kinase (S6K). Importantly, adiponectin treatment increases the expression of tumor suppressor gene, LKB1 in breast cancer cells. LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, its biological functions including inhibition of adhesion, migration and invasion of breast cancer cells. Although further studies are required to analyze the effect of adiponectin on LKB1-AMPK-S6K axis, these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. These results highlight a new role for LKB1 in adiponectin action and may have significant implication for development of novel therapeutic options. Cancer research has largely focused on the molecular basis of oncogenic transformation and tumorigenesis for many years. Recent progress in cancer research has put the metastatic process at the center stage because higher metastatic potential of tumor cells is the major cause of mortality from solid tumors. Metastasis is a complex process that involves modulation of various molecular signaling networks. Tumor cells alter the microenvironment, attain greater cellular adhesion along with better ability to invade and migrate to gain access to circulation. These wandering tumor cells defy anoikis, survive in the circulation, exit into new permissive organ site and colonize distant organs. The microenvironment in which the tumor originates plays an important role in tumor initiation, progression and metastasis.
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PMID:Metastasis suppression by adiponectin: LKB1 rises up to the challenge. 2041 65

Although the role of metabolic syndrome (MS) and a high fat diet in prostate cancer (PCa) risk is still a matter of intense debate, it is becoming increasingly clear that obesity can cause perturbations in metabolic pathways that contribute to the pathogenesis and progression of PCa. Moreover, prostate epithelial cells per se undergo a series of metabolic changes, including an increase in de novo lipogenesis, during the process of tumor formation. These metabolic alterations, at both the cellular and organismal levels, are intertwined with genetic aberrations necessary for neoplastic transformation. Thus, altered metabolism is currently subject to intense research efforts and might provide preventative and therapeutic opportunities, as well as a platform for biomarker development. In this article, we review evidence that the metabolic sensor 5'-AMP-activated protein kinase (AMPK), which physiologically integrates nutritional and hormonal signals and regulates cell survival and growth-related metabolic pathways to preserve intracellular ATP levels, represents a link between energy homeostasis and cancer. Thus, when AMPK is not activated, as in the setting of MS and obesity, systemic metabolic alterations permissive to the development of PCa are allowed to proceed unchecked. Hence, the use of AMPK activators and inhibitors of key lipogenic enzymes may represent a promising therapeutic strategy for PCa.
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PMID:New strategies in prostate cancer: targeting lipogenic pathways and the energy sensor AMPK. 2042 84

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

The relationship between obesity, metabolic syndrome, diabetes and cancer has been recognized for many years. Multiple studies conducted in the last 20 years have identified molecular mechanisms responsible for this phenomenon. Elucidation of the important role of insulin, IGF receptor, mTOR and AMP-activated protein kinase in breast cancer biology has led to the development and subsequent clinical evaluation of novel targeted therapies, including IGF-1 receptor-specific antibodies or tyrosine kinase inhibitors and inhibitors of mTOR. There is also a growing interest in the use of metformin, which has been shown to possess antitumor activity resulting from activation of AMP-activated protein kinase and subsequent inhibiton of mTOR, as well as from decreased circulating insulin levels. Metformin has been shown to inhibit proliferation, invasion and angiogenesis of neoplastic cells and to overcome resistance of breast cancer to chemotherapy, hormonal therapy and HER2 inhibition. Recently, metformin has been demonstrated to inhibit breast cancer stem cell growth and to synergize with chemotherapy in suppression of tumor growth and prolongation of survival of breast tumor-bearing animals. Several currently ongoing Phase II and III clinical studies are evaluating the therapeutic efficacy of metformin in the treatment of early and advanced breast cancer patients.
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PMID:Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. 2046 5

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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