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Chaoguang Tian - One of the best experts on this subject based on the ideXlab platform.
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rco 3 and col 26 form an external to internal module that regulates the dual affinity Glucose Transport System in neurospora crassa
Biotechnology for Biofuels, 2021Co-Authors: Qian Liu, Liangcai Lin, Yongli Zhang, Chaoguang TianAbstract:Background Low- and high-affinity Glucose Transport System is a conserved strategy of microorganism to cope with environmental Glucose fluctuation for their growth and competitiveness. In Neurospora crassa, the dual-affinity Glucose Transport System consists of a low-affinity Glucose Transporter GLT-1 and two high-affinity Glucose Transporters HGT-1/HGT-2, which play diverse roles in Glucose Transport, carbon metabolism, and cellulase expression regulation. However, the regulation of this dual-Transporter System in response to environmental Glucose fluctuation is not yet clear. Results In this study, we report that a regulation module consisting of a downstream transcription factor COL-26 and an upstream non-Transporting Glucose sensor RCO-3 regulates the dual-affinity Glucose Transport System in N. crassa. COL-26 directly binds to the promoter regions of glt-1, hgt-1, and hgt-2, whereas RCO-3 is an upstream factor of the module whose deletion mutant resembles the Δcol-26 mutant phenotypically. Transcriptional profiling analysis revealed that Δcol-26 and Δrco-3 mutants had similar transcriptional profiles, and both mutants had impaired response to a Glucose gradient. We also showed that the AMP-activated protein kinase (AMPK) complex is involved in regulation of the Glucose Transporters. AMPK is required for repression of glt-1 expression in starvation conditions by inhibiting the activity of RCO-3. Conclusions RCO-3 and COL-26 form an external-to-internal module that regulates the Glucose dual-affinity Transport System. Transcription factor COL-26 was identified as the key regulator. AMPK was also involved in the regulation of the dual-Transporter System. Our findings provide novel insight into the molecular basis of Glucose uptake and signaling in filamentous fungi, which may aid in the rational design of fungal strains for industrial purposes.
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rco 3 and col 26 form an external to internal module that regulates the dual affinity Glucose Transport System in neurospora crassa
Biotechnology for Biofuels, 2021Co-Authors: Qian Liu, Liangcai Lin, Yongli Zhang, Chaoguang TianAbstract:Low- and high-affinity Glucose Transport System is a conserved strategy of microorganism to cope with environmental Glucose fluctuation for their growth and competitiveness. In Neurospora crassa, the dual-affinity Glucose Transport System consists of a low-affinity Glucose Transporter GLT-1 and two high-affinity Glucose Transporters HGT-1/HGT-2, which play diverse roles in Glucose Transport, carbon metabolism, and cellulase expression regulation. However, the regulation of this dual-Transporter System in response to environmental Glucose fluctuation is not yet clear. In this study, we report that a regulation module consisting of a downstream transcription factor COL-26 and an upstream non-Transporting Glucose sensor RCO-3 regulates the dual-affinity Glucose Transport System in N. crassa. COL-26 directly binds to the promoter regions of glt-1, hgt-1, and hgt-2, whereas RCO-3 is an upstream factor of the module whose deletion mutant resembles the Δcol-26 mutant phenotypically. Transcriptional profiling analysis revealed that Δcol-26 and Δrco-3 mutants had similar transcriptional profiles, and both mutants had impaired response to a Glucose gradient. We also showed that the AMP-activated protein kinase (AMPK) complex is involved in regulation of the Glucose Transporters. AMPK is required for repression of glt-1 expression in starvation conditions by inhibiting the activity of RCO-3. RCO-3 and COL-26 form an external-to-internal module that regulates the Glucose dual-affinity Transport System. Transcription factor COL-26 was identified as the key regulator. AMPK was also involved in the regulation of the dual-Transporter System. Our findings provide novel insight into the molecular basis of Glucose uptake and signaling in filamentous fungi, which may aid in the rational design of fungal strains for industrial purposes.
Francisco Bolivar - One of the best experts on this subject based on the ideXlab platform.
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metabolic modeling and response surface analysis of an escherichia coli strain engineered for shikimic acid production
BMC Systems Biology, 2018Co-Authors: Juan A Martinez, Noemi Flores, Guillermo Gosset, Alvaro R Lara, Octavio T Ramirez, Alberto Rodriguez, Fabian Moreno, Francisco BolivarAbstract:Classic metabolic engineering strategies often induce significant flux imbalances to microbial metabolism, causing undesirable outcomes such as suboptimal conversion of substrates to products. Several mathematical frameworks have been developed to understand the physiological and metabolic state of production strains and to identify genetic modification targets for improved bioproduct formation. In this work, a modeling approach was applied to describe the physiological behavior and the metabolic fluxes of a shikimic acid overproducing Escherichia coli strain lacking the major Glucose Transport System, grown on complex media. The obtained flux distributions indicate the presence of high fluxes through the pentose phosphate and Entner-Doudoroff pathways, which could limit the availability of erythrose-4-phosphate for shikimic acid production even with high flux redirection through the pentose phosphate pathway. In addition, highly active glyoxylate shunt fluxes and a pyruvate/acetate cycle are indicators of overflow glycolytic metabolism in the tested conditions. The analysis of the combined physiological and flux response surfaces, enabled zone allocation for different physiological outputs within variant substrate conditions. This information was then used for an improved fed-batch process designed to preserve the metabolic conditions that were found to enhance shikimic acid productivity. This resulted in a 40% increase in the shikimic acid titer (60 g/L) and 70% increase in volumetric productivity (2.45 gSA/L*h), while preserving yields, compared to the batch process. The combination of dynamic metabolic modeling and experimental parameter response surfaces was a successful approach to understand and predict the behavior of a shikimic acid producing strain under variable substrate concentrations. Response surfaces were useful for allocating different physiological behavior zones with different preferential product outcomes. Both model sets provided information that could be applied to enhance shikimic acid production on an engineered shikimic acid overproducing Escherichia coli strain.
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Metabolic modeling and response surface analysis of an Escherichia coli strain engineered for shikimic acid production
BMC, 2018Co-Authors: Juan A Martinez, Noemi Flores, Guillermo Gosset, Alvaro R Lara, Octavio T Ramirez, Alberto Rodriguez, Fabian Moreno, Francisco BolivarAbstract:Abstract Background Classic metabolic engineering strategies often induce significant flux imbalances to microbial metabolism, causing undesirable outcomes such as suboptimal conversion of substrates to products. Several mathematical frameworks have been developed to understand the physiological and metabolic state of production strains and to identify genetic modification targets for improved bioproduct formation. In this work, a modeling approach was applied to describe the physiological behavior and the metabolic fluxes of a shikimic acid overproducing Escherichia coli strain lacking the major Glucose Transport System, grown on complex media. Results The obtained flux distributions indicate the presence of high fluxes through the pentose phosphate and Entner-Doudoroff pathways, which could limit the availability of erythrose-4-phosphate for shikimic acid production even with high flux redirection through the pentose phosphate pathway. In addition, highly active glyoxylate shunt fluxes and a pyruvate/acetate cycle are indicators of overflow glycolytic metabolism in the tested conditions. The analysis of the combined physiological and flux response surfaces, enabled zone allocation for different physiological outputs within variant substrate conditions. This information was then used for an improved fed-batch process designed to preserve the metabolic conditions that were found to enhance shikimic acid productivity. This resulted in a 40% increase in the shikimic acid titer (60 g/L) and 70% increase in volumetric productivity (2.45 gSA/L*h), while preserving yields, compared to the batch process. Conclusions The combination of dynamic metabolic modeling and experimental parameter response surfaces was a successful approach to understand and predict the behavior of a shikimic acid producing strain under variable substrate concentrations. Response surfaces were useful for allocating different physiological behavior zones with different preferential product outcomes. Both model sets provided information that could be applied to enhance shikimic acid production on an engineered shikimic acid overproducing Escherichia coli strain
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genetic changes during a laboratory adaptive evolution process that allowed fast growth in Glucose to an escherichia coli strain lacking the major Glucose Transport System
BMC Genomics, 2012Co-Authors: Cesar Aguilar, Adelfo Escalante, Noemi Flores, Ramon De Anda, Fernando Riverosmckay, Guillermo Gosset, Enrique Morett, Francisco BolivarAbstract:Escherichia coli strains lacking the phosphoenolpyruvate: carbohydrate phosphotransferase System (PTS), which is the major bacterial component involved in Glucose Transport and its phosphorylation, accumulate high amounts of phosphoenolpyruvate that can be diverted to the synthesis of commercially relevant products. However, these strains grow slowly in Glucose as sole carbon source due to its inefficient Transport and metabolism. Strain PB12, with 400% increased growth rate, was isolated after a 120 hours adaptive laboratory evolution process for the selection of faster growing derivatives in Glucose. Analysis of the genetic changes that occurred in the PB12 strain that lacks PTS will allow a better understanding of the basis of its growth adaptation and, therefore, in the design of improved metabolic engineering strategies for enhancing carbon diversion into the aromatic pathways. Whole genome analyses using two different sequencing methodologies: the Roche NimbleGen Inc. comparative genome sequencing technique, and high throughput sequencing with Illumina Inc. GAIIx, allowed the identification of the genetic changes that occurred in the PB12 strain. Both methods detected 23 non-synonymous and 22 synonymous point mutations. Several non-synonymous mutations mapped in regulatory genes (arcB, barA, rpoD, rna) and in other putative regulatory loci (yjjU, rssA and ypdA). In addition, a chromosomal deletion of 10,328 bp was detected that removed 12 genes, among them, the rppH, mutH and galR genes. Characterization of some of these mutated and deleted genes with their functions and possible functions, are presented. The deletion of the contiguous rppH, mutH and galR genes that occurred simultaneously, is apparently the main reason for the faster growth of the evolved PB12 strain. In support of this interpretation is the fact that inactivation of the rppH gene in the parental PB11 strain substantially increased its growth rate, very likely by increasing glycolytic mRNA genes stability. Furthermore, galR inactivation allowed Glucose Transport by GalP into the cell. The deletion of mutH in an already stressed strain that lacks PTS is apparently responsible for the very high mutation rate observed.
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current knowledge of the escherichia coli phosphoenolpyruvate carbohydrate phosphotransferase System peculiarities of regulation and impact on growth and product formation
Applied Microbiology and Biotechnology, 2012Co-Authors: Adelfo Escalante, Guillermo Gosset, Ania Salinas Cervantes, Francisco BolivarAbstract:In Escherichia coli, the phosphoenolpyruvate–carbohydrate phosphotransferase System (PTS) is responsible for the Transport and phosphorylation of sugars, such as Glucose. PTS activity has a crucial role in the global signaling System that controls the preferential consumption of Glucose over other carbon sources. When the cell is exposed to carbohydrate mixtures, the PTS prevents the expression of catabolic genes and activity of non-PTS sugars Transport Systems by carbon catabolite repression (CCR). This process defines some metabolic and physiological constraints that must be considered during the development of production strains. In this review, we summarize the importance of the PTS in controlling and influencing both PTS and non-PTS sugar Transport processes as well as the mechanisms of transcriptional control involved in the expression of catabolic genes of non-PTS sugars in E. coli. We discuss three main approaches applied efficiently to avoid these constraints resulting in obtaining PTS− glc+ mutants useful for production purposes: (1) adaptive selection in chemostat culture System of PTS− mutants, resulting in the selection of strains that recovered the ability to grow in Glucose, along with the simultaneous consumption of two carbon sources and reduced acetate production; (2) replacement in PTS− strains of the native GalP promoter by strong promoters or the substitution of this permease by recombinant Glucose Transport System; and (3) enhancement of Crp (crp+) in mgsA, pgi, and ptsG mutants, resulting in derivative strains that abolished CCR, allowing the simultaneous consumption of mixtures of sugars with low acetate production.
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utility of an escherichia coli strain engineered in the substrate uptake System for improved culture performance at high Glucose and cell concentrations an alternative to fed batch cultures
Biotechnology and Bioengineering, 2008Co-Authors: Alvaro R Lara, Guillermo Gosset, Francisco Bolivar, Luis Caspeta, Octavio T RamirezAbstract:Overflow metabolism is an undesirable characteristic of aerobic cultures of Escherichia coli. It results from elevated Glucose consumption rates that cause a high substrate conversion to acetate, severely affecting cell physiology and bioprocess performance. Such phenomenon typically occurs in batch cultures under high Glucose concentration. Fed-batch culture, where Glucose uptake rate is controlled by external addition of Glucose, is the classical bioprocessing alternative to prevent overflow metabolism. Despite its wide-spread use, fed-batch mode presents drawbacks that could be overcome by simpler batch cultures at high initial Glucose concentration, only if overflow metabolism is effectively prevented. In this study, an E. coli strain (VH32) lacking the phosphoenolpyruvate: carbohydrate phosphotransferase System (PTS) with a modified Glucose Transport System was cultured at Glucose concentrations of up to 100 g/L in batch mode, while expressing the recombinant green fluorescence protein (GFP). At the highest Glucose concentration tested, acetate accumulated to a maximum of 13.6 g/L for the parental strain (W3110), whereas a maximum concentration of only 2 g/L was observed for VH32. Consequently, high cell and GFP concentrations of 52 and 8.2 g/L, respectively, were achieved in VH32 cultures at 100 g/L of Glucose. In contrast, maximum biomass and GFP in W3110 cultures only reached 65 and 48%, respectively, of the values attained by the engineered strain. A comparison of this culture strategy against traditional fed-batch culture of W3110 is presented. This study shows that high cell and recombinant protein concentrations are attainable in simple batch cultures by circumventing overflow metabolism through metabolic engineering. This represents a novel and valuable alternative to classical bioprocessing approaches.
Qian Liu - One of the best experts on this subject based on the ideXlab platform.
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rco 3 and col 26 form an external to internal module that regulates the dual affinity Glucose Transport System in neurospora crassa
Biotechnology for Biofuels, 2021Co-Authors: Qian Liu, Liangcai Lin, Yongli Zhang, Chaoguang TianAbstract:Background Low- and high-affinity Glucose Transport System is a conserved strategy of microorganism to cope with environmental Glucose fluctuation for their growth and competitiveness. In Neurospora crassa, the dual-affinity Glucose Transport System consists of a low-affinity Glucose Transporter GLT-1 and two high-affinity Glucose Transporters HGT-1/HGT-2, which play diverse roles in Glucose Transport, carbon metabolism, and cellulase expression regulation. However, the regulation of this dual-Transporter System in response to environmental Glucose fluctuation is not yet clear. Results In this study, we report that a regulation module consisting of a downstream transcription factor COL-26 and an upstream non-Transporting Glucose sensor RCO-3 regulates the dual-affinity Glucose Transport System in N. crassa. COL-26 directly binds to the promoter regions of glt-1, hgt-1, and hgt-2, whereas RCO-3 is an upstream factor of the module whose deletion mutant resembles the Δcol-26 mutant phenotypically. Transcriptional profiling analysis revealed that Δcol-26 and Δrco-3 mutants had similar transcriptional profiles, and both mutants had impaired response to a Glucose gradient. We also showed that the AMP-activated protein kinase (AMPK) complex is involved in regulation of the Glucose Transporters. AMPK is required for repression of glt-1 expression in starvation conditions by inhibiting the activity of RCO-3. Conclusions RCO-3 and COL-26 form an external-to-internal module that regulates the Glucose dual-affinity Transport System. Transcription factor COL-26 was identified as the key regulator. AMPK was also involved in the regulation of the dual-Transporter System. Our findings provide novel insight into the molecular basis of Glucose uptake and signaling in filamentous fungi, which may aid in the rational design of fungal strains for industrial purposes.
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rco 3 and col 26 form an external to internal module that regulates the dual affinity Glucose Transport System in neurospora crassa
Biotechnology for Biofuels, 2021Co-Authors: Qian Liu, Liangcai Lin, Yongli Zhang, Chaoguang TianAbstract:Low- and high-affinity Glucose Transport System is a conserved strategy of microorganism to cope with environmental Glucose fluctuation for their growth and competitiveness. In Neurospora crassa, the dual-affinity Glucose Transport System consists of a low-affinity Glucose Transporter GLT-1 and two high-affinity Glucose Transporters HGT-1/HGT-2, which play diverse roles in Glucose Transport, carbon metabolism, and cellulase expression regulation. However, the regulation of this dual-Transporter System in response to environmental Glucose fluctuation is not yet clear. In this study, we report that a regulation module consisting of a downstream transcription factor COL-26 and an upstream non-Transporting Glucose sensor RCO-3 regulates the dual-affinity Glucose Transport System in N. crassa. COL-26 directly binds to the promoter regions of glt-1, hgt-1, and hgt-2, whereas RCO-3 is an upstream factor of the module whose deletion mutant resembles the Δcol-26 mutant phenotypically. Transcriptional profiling analysis revealed that Δcol-26 and Δrco-3 mutants had similar transcriptional profiles, and both mutants had impaired response to a Glucose gradient. We also showed that the AMP-activated protein kinase (AMPK) complex is involved in regulation of the Glucose Transporters. AMPK is required for repression of glt-1 expression in starvation conditions by inhibiting the activity of RCO-3. RCO-3 and COL-26 form an external-to-internal module that regulates the Glucose dual-affinity Transport System. Transcription factor COL-26 was identified as the key regulator. AMPK was also involved in the regulation of the dual-Transporter System. Our findings provide novel insight into the molecular basis of Glucose uptake and signaling in filamentous fungi, which may aid in the rational design of fungal strains for industrial purposes.
Timothy W Garvey - One of the best experts on this subject based on the ideXlab platform.
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nr4a orphan nuclear receptors modulate insulin action and the Glucose Transport System potential role in insulin resistance
Journal of Biological Chemistry, 2007Co-Authors: Liehong Luo, Nanlan Luo, Xiaolin Zhu, Timothy W GarveyAbstract:After observing that expression of two NR4A orphan nuclear receptors, NR4A3 and NR4A1, was altered by insulin in cDNA microarray analyses of human skeletal muscle, we studied whether these receptors could modulate insulin sensitivity. We found that both NR4A3 and NR4A1 were induced by insulin and by thiazolidinedione drugs (pioglitazone and troglitazone) in 3T3-L1 adipocytes. Furthermore, gene expression of NR4A3 and NR4A1 was reduced in skeletal muscles and adipose tissues from multiple rodent models of insulin resistance. To determine whether NR4A3 could modulate insulin sensitivity, 3T3-L1 adipocytes were stably transduced with NR4A3 or LacZ (control) lentiviral vectors. Compared with LacZ expressing cells, hyperexpression of NR4A3 increased the ability of insulin to augment Glucose Transport activity, and the mechanism involved increased recruitment of GLUT4 Glucose Transporters to the plasma membrane. NR4A3 hyperexpression also led to an increase in insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 as well as Akt phosphorylation. Suppression of NR4A3 using lentiviral short hairpin RNA constructs reduced the ability of insulin to stimulate Glucose Transport and phosphorylate Insulin receptor substrate-1 and Akt. Thus, NR4A3 and NR4A1 are attractive novel therapeutic targets for potential amelioration of insulin resistance, and treatment and prevention of type 2 diabetes and the metabolic syndrome.
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adiponectin promotes adipocyte differentiation insulin sensitivity and lipid accumulation
Journal of Lipid Research, 2005Co-Authors: Nanlan Luo, Richard L Klein, Timothy W GarveyAbstract:Adiponectin is secreted from adipocytes, and low circulating levels have been epidemiologically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. To investigate whether adiponectin could exert autocrine effects in adipocytes, we expressed the adiponectin gene in 3T3-L1 fibroblasts. We observed that 3T3-L1 fibroblasts expressing adiponectin have a fast growth phase and reach confluence more rapidly compared with control cells or LacZ-transduced cells. Furthermore, cells with overexpressed adiponectin were observed to differentiate into adipocytes more rapidly, and during adipogenesis, they exhibited more prolonged and robust gene expression for related transcriptional factors, CCAAT/enhancer binding protein alpha (C/EBP2), peroxisome proliferator-activated receptor gamma (PPARgamma), and adipocyte determination and differentiation factor 1/sterol-regulatory element binding protein 1c (ADD1/SREBP1c) and earlier suppression of PPARgamma coactivator-1alpha (PGC-1alpha). In fully differentiated adipocytes, adiponectin-overexpressing cells accumulated more and larger lipid droplets compared with control cells. Also, adiponectin increased insulin's ability to maximally stimulate Glucose uptake by 78% through increased Glucose Transporter 4 (GLUT4) gene expression and increased GLUT4 recruitment to the plasma membrane. These data suggest a new role for adiponectin as an autocrine factor in adipose tissues: promoting cell proliferation and differentiation from preadipocytes into adipocytes, augmenting programmed gene expression responsible for adipogenesis, and increasing lipid content and insulin responsiveness of the Glucose Transport System in adipocytes.
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adipocytes exhibit abnormal subcellular distribution and translocation of vesicles containing Glucose Transporter 4 and insulin regulated aminopeptidase in type 2 diabetes mellitus implications regarding defects in vesicle trafficking
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Lidia Maianu, Susanna R Keller, Timothy W GarveyAbstract:Insulin resistance in type 2 diabetes is due to impaired stimulation of the Glucose Transport System in muscle and fat. Different defects are operative in these two target tissues because Glucose Transporter 4 (GLUT 4) expression is normal in muscle but markedly reduced in fat. In muscle, GLUT 4 is redistributed to a dense membrane compartment, and insulin-mediated translocation to plasma membrane (PM) is impaired. Whether similar trafficking defects are operative in human fat is unknown. Therefore, we studied subcellular localization of GLUT4 and insulin-regulated aminopeptidase (IRAP; also referred to as vp165 or gp160), which is a constituent of GLUT4 vesicles and also translocates to PM in response to insulin. Subcutaneous fat was obtained from eight normoglycemic control subjects (body mass index, 29 +/- 2 kg/m2) and eight type 2 diabetic patients (body mass index, 30 +/- 1 kg/m2; fasting Glucose, 14 +/- 1 mM). In adipocytes isolated from diabetics, the basal 3-O-methylGlucose Transport rate was decreased by 50% compared with controls (7.1 +/- 2.9 vs. 14.1 +/- 3.7 mmol/mm2 surface area/min), and there was no increase in response to maximal insulin (7.9 +/- 2.7 vs. 44.5 +/- 9.2 in controls). In membrane subfractions from controls, insulin led to a marked increase of IRAP in the PM from 0.103 +/- 0.04 to 1.00 +/- 0.33 relative units/mg protein, concomitant with an 18% decrease in low-density microsomes and no change in high-density microsomes (HDM). In type 2 diabetes, IRAP overall expression in adipocytes was similar to that in controls; however, two abnormalities were observed. First, in basal cells, IRAP was redistributed away from low-density microsomes, and more IRAP was recovered in HDM (1.2-fold) and PM (4.4-fold) from diabetics compared with controls. Second, IRAP recruitment to PM by maximal insulin was markedly impaired. GLUT4 was depleted in all membrane subfractions (43-67%) in diabetes, and there was no increase in PM GLUT4 in response to insulin. Type 2 diabetes did not affect the fractionation of marker enzymes. We conclude that in human adipocytes: 1) IRAP is expressed and translocates to PM in response to insulin; 2) GLUT4 depletion involves all membrane subfractions in type 2 diabetes, although cellular levels of IRAP are normal; and 3) in type 2 diabetes, IRAP accumulates in membrane vesicles cofractionating with HDM and PM under basal conditions, and insulin-mediated recruitment to PM is impaired. Therefore, in type 2 diabetes, adipocytes express defects in trafficking of GLUT4/IRAP-containing vesicles similar to those causing insulin resistance in skeletal muscle.
Erik J Henriksen - One of the best experts on this subject based on the ideXlab platform.
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the role of the renin angiotensin System in the development of insulin resistance in skeletal muscle
Molecular and Cellular Endocrinology, 2013Co-Authors: Erik J Henriksen, Mujalin PrasannarongAbstract:The canonical renin-angiotensin System (RAS) involves the initial action of renin to cleave angiotensinogen to angiotensin I (ANG I), which is then converted to ANG II by the angiotensin converting enzyme (ACE). ANG II plays a critical role in numerous physiological functions, and RAS overactivity underlies many conditions of cardiovascular dysregulation. In addition, ANG II, by acting on both endothelial and myocellular AT1 receptors, can induce insulin resistance by increasing cellular oxidative stress, leading to impaired insulin signaling and insulin-stimulated Glucose Transport activity. This insulin resistance associated with RAS overactivity, when coupled with progressive s-cell dysfunction, eventually leads to the development of type 2 diabetes. Interventions that target RAS overactivity, including ACE inhibitors, ANG II receptor blockers, and, most recently, renin inhibitors, are effective both in reducing hypertension and in improving whole-body and skeletal muscle insulin action, due at least in part to enhanced Akt-dependent insulin signaling and insulin-dependent Glucose Transport activity. ANG-(1-7), which is produced from ANG II by the action of ACE2 and acts via Mas receptors, can counterbalance the deleterious actions of the ACE/ANG II/AT1 receptor axis on the insulin-dependent Glucose Transport System in skeletal muscle. This beneficial effect of the ACE2/ANG-(1-7)/Mas receptor axis appears to depend on the activation of Akt. Collectively, these findings underscore the importance of RAS overactivity in the multifactorial etiology of insulin resistance in skeletal muscle, and provide support for interventions that target the RAS to ameliorate both cardiovascular dysfunctions and insulin resistance in skeletal muscle tissue.
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effects of in vitro antagonism of endocannabinoid 1 receptors on the Glucose Transport System in normal and insulin resistant rat skeletal muscle
Diabetes Obesity and Metabolism, 2010Co-Authors: Katherine A Lindborg, Stephan Jacob, Mary K Teachey, Erik J HenriksenAbstract:OBJECTIVE: We determined the direct effects of modulating the endocannabinoid-1 (CB1) receptor on the Glucose Transport System in isolated skeletal muscle from insulin-sensitive lean Zucker and insulin-resistant obese Zucker rats. METHODS: Soleus strips were incubated in the absence or presence of insulin, without or with various concentrations of the CB1 receptor antagonist SR141716 or with the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA). RESULTS: CB1 receptor protein expression in visceral adipose (57%), soleus (40%) and myocardial (36%) tissue was significantly (p < 0.05) decreased in obese compared to lean animals, with a trend for a reduction (17%, p = 0.079) in the liver. In isolated soleus muscle from both lean and obese Zucker rats, CB1 receptor antagonism directly improved Glucose Transport activity in a dose-dependent manner. Basal Glucose Transport activity was maximally enhanced between 100 and 200 nM SR141716 in lean (26-28%) and obese (22-31%) soleus. The maximal increase in insulin-stimulated Glucose Transport for lean muscle ( approximately 30%) was achieved at 50 nM SR141716 and for obese muscle ( approximately 30%) at 100 nM SR141716. In contrast, CB1 receptor antagonism did not alter hypoxia-stimulated Glucose Transport activity. CB1 receptor agonism (1 mM ACEA) significantly decreased both basal (15%) and insulin-stimulated (22%) Glucose Transport activity in isolated lean soleus. This effect was reversed by 200 nM SR141716. In both lean and obese muscle, the functionality of key signalling proteins (insulin receptor beta-subunit, Akt, glycogen synthase kinase-3beta (GSK-3beta), AMP-dependent protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK)) was not altered by either CB1 receptor agonism or antagonism. CONCLUSION: These results indicate that the engagement of CB1 receptor can negatively modulate both basal and insulin-dependent Glucose Transport activity in lean and obese skeletal muscles, and that these effects are not mediated by the engagement of elements of the canonical pathways regulating this process in mammalian skeletal muscle.
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modulation of metabolic control by angiotensin converting enzyme ace inhibition
Journal of Cellular Physiology, 2003Co-Authors: Erik J Henriksen, Stephan JacobAbstract:Angiotensin converting enzyme (ACE) inhibitors are a widely used intervention for blood pressure control, and are particularly beneficial in hypertensive type 2 diabetic subjects with insulin resistance. The hemodynamic effects of ACE inhibitors are associated with enhanced levels of the vasodilator bradykinin and decreased production of the vasoconstrictor and growth factor angiotensin II (ATII). In insulin-resistant conditions, ACE inhibitors can also enhance whole-body Glucose disposal and Glucose Transport activity in skeletal muscle. This review will focus on the metabolic consequences of ACE inhibition in insulin resistance. At the cellular level, ACE inhibitors acutely enhance Glucose uptake in insulin-resistant skeletal muscle via two mechanisms. One mechanism involves the action of bradykinin, acting through bradykinin B2 receptors, to increase nitric oxide (NO) production and ultimately enhance Glucose Transport. A second mechanism involves diminution of the inhibitory effects of ATII, acting through AT1 receptors, on the skeletal muscle Glucose Transport System. The acute actions of ACE inhibitors on skeletal muscle Glucose Transport are associated with upregulation of insulin signaling, including enhanced IRS-1 tyrosine phosphorylation and phosphatidylinositol-3-kinase activity, and ultimately with increased cell-surface GLUT-4 Glucose Transporter protein. Chronic administration of ACE inhibitors or AT1 antagonists to insulin-resistant rodents can increase protein expression of GLUT-4 in skeletal muscle and myocardium. These data support the concept that ACE inhibitors can beneficially modulate Glucose control in insulin-resistant states, possibly through a NO-dependent effect of bradykinin and/or antagonism of ATII action on skeletal muscle. © 2003 Wiley-Liss, Inc.