5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

Gaidhu, Mandeep Pinky; Fediuc, Sergiu; Ceddia, Rolando B.

doi:10.1074/jbc.m602992200

Cited by 103 publications

(108 citation statements)

References 35 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Activation of AMPK by AICAR has been shown to inhibit lipolysis and lipogenesis in vitro in adipocytes [8,24,25] and in vivo in both lean and insulin-resistant obese rat models [5]. This study is the first to demonstrate that i.v.…”

Section: Discussionmentioning

confidence: 68%

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis The 5′-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients.Methods Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg −1 min −1 ) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64±2 years; BMI 28±1 kg/m 2 ). Results Plasma glucose rate of appearance (R a ) was reduced following AICAR administration, while plasma glucose rate of disappearance (R d ) was similar in the AICAR and control test. Consequently, blood glucose disposal (R d expressed as a percentage of R a ) was increased following AICAR infusion (p<0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p<0.001). Plasma NEFA R a and R d were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p<0.001). Conclusions/interpretation The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

show abstract

Section: Discussionmentioning

confidence: 68%

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

et al. 2008

View full text Add to dashboard Cite

show abstract

“…This concept has been well illustrated in muscle and liver; however, its applicability to the adipocyte has been less explored (70). Some reports suggest that AMPK inhibits lipid (71)(72)(73) and protein synthesis (74) in adipocytes as it does in other cells. Its effects on glucose transport and fatty acid oxidation in the adipocyte are less clear (72,(75)(76)(77).…”

Section: Discussionmentioning

confidence: 99%

“…Some reports suggest that AMPK inhibits lipid (71)(72)(73) and protein synthesis (74) in adipocytes as it does in other cells. Its effects on glucose transport and fatty acid oxidation in the adipocyte are less clear (72,(75)(76)(77). Another means by which AMPK could restrain energy depletion in adipocytes is by reducing lipolysis.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

225

207

View full text Add to dashboard Cite

AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis. AMP-activated protein kinase (AMPK)2 is a sensor of cellular energy state that responds to metabolic stresses and other regulatory signals. The mechanism of activation of AMPK is a complex phenomenon and is still not fully understood, although it is recognized that it involves phosphorylation of the critical Thr-172 residue of its ␣ catalytic subunit by upstream kinases such as LKB1, Ca 2ϩ -calmodulin-dependent protein kinase kinase, and possibly Tak1, a member of the mitogenactivated protein kinase kinase kinase family (1-5). AMPK is also regulated by AMP allosterically and the current view is that this both increases AMPK activity directly and makes it a poorer substrate for phosphatases (6).The role and regulation of AMPK in muscle, liver, and various cultured cells have been extensively studied. It is now well established that energy depletion because of starvation, hypoxia, and exercise increases the intracellular AMP:ATP ratio and secondarily AMPK activity (7). Upon its activation, a major role of AMPK is to replete cellular energy stores by stimulating processes that generate ATP, such as fatty acid oxidation, and inhibiting ATP-consuming pathways (e.g. lipogenesis, triglyceride synthesis, and gluconeogenesis) that are not acutel...

show abstract

“…However, the findings in adipose tissue are controversial. Under basal conditions (no insulin stimulation), several studies have reported that the activation of AMPK by AICAR accelerates GLUT4 translocation and increases glucose uptake [23,24] , whereas others have shown that glucose uptake is suppressed by activated AMPK in adipocytes, probably due to decreased translocation of GLUT4 [51] .…”

Section: Wwwchinapharcom Feng L Et Almentioning

confidence: 99%

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Song

Guan

et al. 2010

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim:The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF2A, D) as mediators of the effects of ethanol on glucose transporter 4 (GLUT4) expression are unclear. We studied the effects of ethanol in adipocytes in vivo and in vitro. Methods: Thirty-six male Wistar rats were divided into three groups and given ethanol in a single daily dose of 0, 0.5, or 5 g/kg for 22 weeks. The expression of AMPK, MEF2 isoforms A and D, and GLUT4 was measured and compared in the three groups. The existence of the AMPK/MEF2/GLUT4 pathway in adipocytes and the effects of ethanol on this pathway were studied in (a) epididymal adipose tissue from six male Wistar rats subcutaneously injected with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, an AMPK activator) or with 0.9% NaCl (control); and (b) isolated rat and human adipocytes treated with or without ethanol, AICAR, and compound C (a selective AMPK inhibitor). Expression of AMPK, MEF2, and GLUT4 was measured by RT-PCR and Western blotting. Results: (1) Long-term ethanol exposure decreased activated AMPK, MEF2A, MEF2D, and GLUT4 expression in rat adipose tissue. (2) In rat and human adipocytes, AICAR-induced AMPK activation, with subsequent elevation of MEF2 and GLUT4 expression, was inhibited by compound C. (3) In vitro ethanol-treatment suppressed the AMPK/MEF2/GLUT4 pathway. Conclusion: The AMPK/MEF2/GLUT4 pathway exists in both rat and human adipocytes, and activated AMPK may positively regulate MEF2 and GLUT4 expression. Ethanol inhibition of this pathway leads to decreased GLUT4 expression, thus reducing insulin sensitivity and glucose tolerance.

show abstract

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-induced AMP-activated Protein Kinase Phosphorylation Inhibits Basal and Insulin-stimulated Glucose Uptake, Lipid Synthesis, and Fatty Acid Oxidation in Isolated Rat Adipocytes

Cited by 103 publications

References 35 publications

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Contact Info

Product

Resources

About